PINP as a biological response marker during teriparatide treatment for osteoporosis

Abstract

Postmenopausal women with severe osteoporosis may require treatment with the bone anabolic drug teriparatide. While changes in bone mineral density (BMD) are one measure of response, BMD changes often require a minimum of one year to observe measureable changes. Biochemical markers of bone turnover change within 1 to 3 months of initiating osteoporosis therapy. Monitoring with a marker such as procollagen type I N propeptide (PINP), an osteoblast-derived protein, during teriparatide treatment may provide clinically useful information for managing patients with osteoporosis. Clinical trials have shown consistent increases in PINP within 3 months of initiating teriparatide, increases that are significantly greater than placebo and significantly different from baseline. Increases in PINP concentrations during teriparatide treatment correlate well with increases in skeletal activity assessed by radioisotope bone scans and quantitative bone histomorphometry parameters. Individuals treated with teriparatide in clinical trials usually experienced an increase in PINP > 10 mcg/L from baseline, while those given placebo usually did not. In the clinical setting, patients experiencing a significant increase in PINP > 10 mcg/L after initiating teriparatide therapy may receive an earlier confirmation of anabolic effect, while those who do not may be assessed for adherence, proper injection technique, or undetected secondary conditions that might mitigate an anabolic response. PINP monitoring may provide information supplemental to BMD monitoring and be a useful aid in managing patients receiving anabolic osteoporosis treatment in the same way that biochemical markers of bone resorption are useful in monitoring antiresorptive therapy. This review examines PINP as a biological response marker during teriparatide treatment for osteoporosis.

Fig. 1

Type 1 collagen formation and procollagen type I N propeptide (PINP). Type 1 procollagen is made in the osteoblast and secreted into new bone matrix. In the bone matrix, procollagen peptidases cleave PINP from the amino (N) terminal end and procollagen type I C propeptide (PICP) from the carboxy (C)-terminal end of type 1 procollagen, resulting in mature type 1 collagen. Mature type 1 collagen is the most common protein in bone; a triple helical structure composed of two alpha-1 chains and one alpha-2 chain. PINP and PICP make their way into the circulation. Within the circulation, PINP exists as different linear forms including the original intact trimeric PINP and the monomeric or dimeric degradation products. Available PINP assays measure either intact triple helical PINP or total PINP, which includes intact PINP as well as the other forms of PINP. With permission from Bauer et al. [13]

Fig. 2

Signal-to-noise ratio for biological markers of bone turnover measured at 3 months in the Fracture Prevention Trial of postmenopausal women with osteoporosis. Bone turnover markers other than PINP were measured in a subset of 171 women in the teriparatide 20 mcg/day group and 175 women in the placebo group. PINP was measured in a subset of 254 women in the teriparatide 20 mcg/day group and 260 women in the placebo group from samples that had been stored frozen for at least 4 years and had been previously thawed at least twice [17]. DPD urinary deoxypyridine corrected for creatinine, NTX-I urinary N-terminal cross-linking telopeptide of type I collagen corrected for creatinine, Bone ALP bone alkaline phosphatase, PICP procollagen type I C propeptide, PINP intact procollagen type I N propeptide. Adapted from Eastell and colleagues [17]

Fig. 3

Typical effects of teriparatide on bone formation and bone resorption markers during teriparatide treatment in postmenopausal women with osteoporosis. Percentage change (adjusted least squares mean ± standard error) from baseline in serum PINP and urinary NTX-I in patients treated with teriparatide. PINP intact procollagen type I N propeptide, NTX-I urinary N-terminal cross-linking telopeptide of type I collagen corrected for creatinine. ^* p < 0.001, ^** p < 0.050 for change from baseline within-group comparisons. Adapted from McClung and colleagues [35]

Fig. 4

Changes in intact PINP in a trial of Japanese patients with osteoporosis randomized to teriparatide or to placebo. Median change from baseline in PINP. PINP intact procollagen type I N propeptide, IQR interquartile range. ^* p < 0.001for within-group comparisons. The I-bars represent interquartile ranges (25th, 75th percentile). Adapted from Tsujimoto and colleagues [39]

Fig. 5

Correlation between procollagen type I N propeptide (PINP) change from baseline to 1 month (mcg/L) and percent change in lumbar spine bone mineral density (BMD) from baseline to 12 months in a trial of Japanese patients with osteoporosis randomized to teriparatide or to placebo. A vertical line represents a PINP increase of 10 mcg/L, and a horizontal line represents a lumbar spine BMD increase of 3 %. Adapted from Tsujimoto and colleagues [39]

Fig. 6

Vertebral fracture outcomes at 36 months from a trial of glucocorticoid-induced osteoporosis patients randomized to alendronate or to teriparatide. The left side of the figure represents data by treatment group assignment. The right side of the figure represents data for a subset of patients (N = 199) who had PINP assessments at baseline, 1, and 6 months, designating PINP increment from baseline >10 mcg/L at 1 or 6 months. TPTD teriparatide, ALN alendronate,PINP intact procollagen type I N propeptide. Adapted from Saag and colleagues [49]

Fig. 7

Simplified approach to using PINP to assess osteoporosis patients treated with teriparatide. PINP is a biological response marker indicating whether bone formation has increased between baseline and follow-up measurements in a patient treated with teriparatide. A biological response marker is not a surrogate marker of efficacy, which would predict future outcomes like fracture. PINP intact procollagen type I N propeptide