Teriparatide for osteoporosis: importance of the full course

Abstract

Teriparatide (TPTD) is the only currently available therapeutic agent that increases the formation of new bone tissue and can provide some remediation of the architectural defects in the osteoporotic skeleton. The use of teriparatide clinically is limited to 24 months. We review clinical findings during daily teriparatide treatment over time. Teriparatide appears to increase bone formation more than bone resorption as determined biochemically and histologically. Teriparatide exerts its positive effects on bone formation in two distinct fashions. The first is direct stimulation of bone formation that occurs within active remodeling sites (remodeling-based bone formation) and on surfaces of bone previously inactive (modeling-based bone formation). The second is an increase in the initiation of new remodeling sites. Both processes contribute to the final increase in bone density observed by non-invasive tools such as DXA. Remodeling is the repair process by which skeletal tissue is maintained in a young healthy state, and when stimulated by TPTD is associated with a positive bone balance within each remodeling cavity. It seems likely therefore that this component will contribute to the anti-fracture efficacy of TPTD. Teriparatide reduces the risk of fracture, and this effect appears to increase with longer duration of therapy. The use of novel treatment regimens, including shorter courses, should be held in abeyance until controlled clinical trials are completed to define the relative fracture benefits of such approaches in comparison to the 24-month daily use of the agent. Summary In patients with osteoporosis at high risk for fracture, the full continuous 24-month course with teriparatide results in improved skeletal health and outcomes than shorter time periods.

Keywords: Bone histomorphometry; Fracture; Osteoporosis; Teriparatide.

Fig. 1

Changes in biochemical markers of bone turnover in patients treated with teriparatide. Solid lines indicate treatment-naïve patients (n = 16), and dotted lines indicate alendronate-pre-treated patients (n = 29). X axes have been scaled to allow comparisons of relative changes to reference ranges. *p < 0.05 versus from baseline, ^† p < 0.05 between groups. PINP procollagen I N-terminal propeptide, CTX type 1 collagen cross-linked C-telopeptide. Reproduced with permission from Stepan JJ et al. [15]

Fig. 2

Bone formation in post-menopausal women with osteoporosis treated with teriparatide as reflected by mineralizing surface divided by bone surface (MS/BS%) at cancellous, endocortical, intracortical, and periosteal compartments. The study included 29 patients previously treated with alendronate and 16 patients naive to previous osteoporosis treatment. Results are means ± SEM shown for each group and for the two groups pooled together (the latter previously unpublished). P values are for comparisons of baseline versus the 24-month treatment period. The data is from the study published by Stepan et al. [15] and Ma et al. [23]

Fig. 3

This figure shows previously unpublished iliac crest bone biopsy specimens from a patient treated with teriparatide 20 mcg/day to illustrate two fundamental anabolic actions: a unstained fluorescence light image and b transmitted light for toluidine blue staining image specific for cement lines. Newly formed lamellar bone is indicated by the yellow arrows. Smooth cement lines and parallel collagen fiber orientation versus the adjacent bone tissue, without interruption, indicate that this bone formation is related to bone modeling or the deposition of new bone on a previously quiescent bone surface. c Unstained fluorescence light image and d transmitted light for toluidine blue staining image specific for cement lines. Scalloped cement line shown by red arrows represents previous resorption surface, and the smooth cement line in the adjacent bone illustrated by yellow arrows illustrates the spilling of new bone formation onto an adjacent surface. The mixture of scalloped cement lines transitioning to smooth cement lines is indicative of overfilling of a remodeling site onto the adjacent bone surface. These previously unpublished images from the study described by Ma et al. [32] are courtesy of Dr. Linda Ma

Fig. 4

Increase in cancellous bone volume divided by total volume and cortical thickness from baseline through 24 months of teriparatide treatment and included patients previously treated with alendronate and patients naïve to previous osteoporosis treatment. Results are means ± SEM shown for each group and for the two groups pooled together (the latter previously unpublished). P values are for comparisons of baseline versus the 24-month treatment period. Results are from Stepan et al. [15] and Ma et al. [23]

Fig. 5

Adjusted mean BMD changes from baseline after 24 months of continuous teriparatide treatment stratified by previous predominant treatment. Numbers at top vertical bars indicate percent change from baseline. a Lumbar spine, p < 0.001 for all within-treatment group changes from baseline at all time points. Between-group comparisons at 6, 12, 18, and 24 months, p < 0.05 etidronate (ETI) versus alendronate (ALN) and ETI versus risedronate (RIS) and p < 0.05 ETI versus non-bisphosphonate (NONBP) at 18 and 24 months. All other between-group comparisons were not statistically significant. b Femoral neck, p < 0.05 for ALN versus ETI between-group comparison at 18 months. All other between-group comparisons were not statistically significant. Error bars indicate SEM. *p < 0.001 for within-treatment group change from baseline, ^† p < 0.05 within-treatment group change from baseline. Reproduced with permission from Boonen et al. [50]

Fig. 6

Rectangular “virtual biopsies” taken using high-resolution CT scan images of the 12th thoracic vertebra at baseline and after 6, 12, and 24 months of treatment with teriparatide show a progressive increase in bone mass. These previously unpublished images kindly provided by Professors Claus C. Glüer and Christian Graeff, University SH Kiel, Germany, are from the study described by Graeff et al. [56]