Teriparatide (PTH 1-34) treatment increases peripheral hematopoietic stem cells in postmenopausal women

Abstract

Cells of the osteoblast lineage play an important role in regulating the hematopoietic stem cell (HSC) niche and early B-cell development in animal models, perhaps via parathyroid hormone (PTH)-dependent mechanisms. There are few human clinical studies investigating this phenomenon. We studied the impact of long-term daily teriparatide (PTH 1-34) treatment on cells of the hematopoietic lineage in postmenopausal women. Twenty-three postmenopausal women at high risk of fracture received teriparatide 20 mcg sc daily for 24 months as part of a prospective longitudinal trial. Whole blood measurements were obtained at baseline, 3, 6, 12, and 18 months. Flow cytometry was performed to identify hematopoietic subpopulations, including HSCs (CD34+/CD45(moderate); ISHAGE protocol) and early transitional B cells (CD19+, CD27-, IgD+, CD24[hi], CD38[hi]). Serial measurements of spine and hip bone mineral density (BMD) as well as serum P1NP, osteocalcin, and CTX were also performed. The average age of study subjects was 64 ± 5 years. We found that teriparatide treatment led to an early increase in circulating HSC number of 40% ± 14% (p = 0.004) by month 3, which persisted to month 18 before returning to near baseline by 24 months. There were no significant changes in transitional B cells or total B cells over the course of the study period. In addition, there were no differences in complete blood count profiles as quantified by standard automated flow cytometry. Interestingly, the peak increase in HSC number was inversely associated with increases in bone markers and spine BMD. Daily teriparatide treatment for osteoporosis increases circulating HSCs by 3 to 6 months in postmenopausal women. This may represent a proliferation of marrow HSCs or increased peripheral HSC mobilization. This clinical study establishes the importance of PTH in the regulation of the HSC niche within humans. © 2014 American Society for Bone and Mineral Research.

Trial registration: ClinicalTrials.gov NCT00926380.

Keywords: B CELL LYMPHOPOIESIS; HEMATOPOIETIC STEM CELL NICHE; PARATHYROID HORMONE; TERIPARATIDE.

© 2014 American Society for Bone and Mineral Research.

Figures

Figure 1. Peripheral Hematopoietic Stem Cells (HSCs) during 24 months of teriparatide treatment

HSCs were assessed by flow cytometry at months 0 (n=18), 3 (n=18), 6 (n=17), 12 (n=13), 18 (n=15), and 24 (n=15) after initiation of daily teriparatide. Increases in HSCs over baseline are evident at months 3 (p=0.004), 6 (p=0.013), and 18 (p=0.044; * indicates statistical significance after Dunnett’s adjustment for multiple comparisons). HSC number declines towards baseline by 24 months of daily teriparatide treatment. Data presented are mean ± SEM.

Figure 2. B and T lymphocyte subpopulations during 12 months of teriparatide treatment

B and T lymphocytes were assessed by flow cytometry at months 0 (n=23), 3 (n=22), 6 (n=21), and 12 (n=19) after initiation of daily teriparatide. No significant changes were noted in early transitional B cells, total B cells, or total T cells in response to daily teriparatide treatment. Data presented are mean ± SEM.

Figure 3. Other hematopoietic lineages during 24 months of teriparatide treatment

Complete blood counts with differentials were assessed by standard automated flow cytometry at months 0 (n=23), 3 (n=23), 6 (n=22), 12 (n=21), 18 (n=20), and 24 (n=20) after initiation of daily teriparatide. No significant changes were noted in total white blood cells, lymphocytes, monocytes, neutrophils, red blood cells, or platelets in response to daily teriparatide treatment. Data presented are mean ± SEM.

Figure 4. Inverse correlation of change in HSCs with change in bone markers

Both HSCs and bone markers increased during the initial period of teriparatide treatment before reaching a plateau and subsequently declining. Peak change in HSCs at 3 months was inversely correlated with change in P1NP, Osteocalcin, and CTX at 3 months.

Figure 5. Inverse correlation of change in HSCs with change in bone density

HSC number during teriparatide treatment peaked at 3 months, whereas bone density increased throughout the 24 months. Peak change in HSCs at 3 months was inversely correlated with change in PA spine BMD at 24 months, but was not associated with change in total hip or femoral neck BMD.