Anabolic action of parathyroid hormone (PTH) does not compromise bone matrix mineral composition or maturation

Abstract

Intermittent administration of parathyroid hormone (PTH) is used to stimulate bone formation in patients with osteoporosis. A reduction in the degree of matrix mineralisation has been reported during treatment, which may reflect either production of undermineralised matrix or a greater proportion of new matrix within the bone samples assessed. To explore these alternatives, high resolution synchrotron-based Fourier Transform Infrared Microspectroscopy (sFTIRM) coupled with calcein labelling was used in a region of non-remodelling cortical bone to determine bone composition during anabolic PTH treatment compared with region-matched samples from controls. 8week old male C57BL/6 mice were treated with vehicle or 50μg/kg PTH, 5 times/week for 4weeks (n=7-9/group). Histomorphometry confirmed greater trabecular and periosteal bone formation and 3-point bending tests confirmed greater femoral strength in PTH-treated mice. Dual calcein labels were used to match bone regions by time-since-mineralisation (bone age) and composition was measured by sFTIRM in six 15μm regions at increasing depth perpendicular to the most immature bone on the medial periosteal edge; this allowed in situ measurement of progressive changes in bone matrix during its maturation. The sFTIRM method was validated in vehicle-treated bones where the expected progressive increases in mineral:matrix ratio and collagen crosslink type ratio were detected with increasing bone maturity. We also observed a gradual increase in carbonate content that strongly correlated with an increase in longitudinal stretch of the collagen triple helix (amide I:amide II ratio). PTH treatment did not alter the progressive changes in any of these parameters from the periosteal edge through to the more mature bone. These data provide new information about how the bone matrix matures in situ and confirm that bone deposited during PTH treatment undergoes normal collagen maturation and normal mineral accrual.

Effects of Parathyroid Hormone, Alendronate and Odanacatib on the mineralisation process in intracortical and endocortical Haversian bone of ovariectomized rabbits

“…PTH treatment did not alter mineral accrual, carbonate substitution or amide I:II ratio in endocortical bone, consistent with our previous observations in murine periosteum [16]. mineral:matrix levels continued to increase in deeper regions of bone (see Figure 3C, PTH); this indicates that PTH treatment has restored the normal bone maturation pattern that was lost in OVX rabbits (see Figure 3C, vehicle).…”

“…Synchrotron-based FTIRM analysis of recently formed endocortical bone in Shamoperated rabbits demonstrated the same three characteristics of bone matrix maturation that we previously observed in recently formed bone on the murine periosteum [16]: (1) mineral accrual, (2) carbonate substitution, and (3) collagen compaction, indicated by amide I:II suppression ( Figure 3A, 4A, 5A). Carbonate substitution, indicated by carbonate:mineral ratio, gradually increased with increasing bone age at all sites measured ( Figure 4A-C).…”

Autocrine and Paracrine Regulation of the Murine Skeleton by Osteocyte-Derived Parathyroid Hormone-Related Protein

“…All these ideas require further investigation. We suggest PTHrP affects cortical strength through non–receptor‐mediated signaling because intermittent PTH administration, which would also act through PTHR1, did not change bone matrix composition or material strength in mice apart from its ability to increase bone mass …”

“…We suggest PTHrP affects cortical strength through non-receptor-mediated signaling because intermittent PTH administration, which would also act through PTHR1, did not change bone matrix composition or material strength in mice apart from its ability to increase bone mass. (80) Our discovery of full-length PTHrP production and secretion by osteocytes provides a way to distinguish the skeletal effects of locally-produced PTHrP from circulating PTH. Although both act on PTHR1, they differ in their roles in skeletal physiology and pathology.…”

Abaloparatide Is an Anabolic, but Does It Spare Resorption?

“…Indeed, BMD often decreases during teriparatide therapy as bone matrix volume increases, in part, because of an increase in porosity and the replacement of older, more mineralized bone with a larger volume of younger, initially less mineralized bone matrix. (60) The rise in BMD is the net result of an increase in bone matrix volume, any modeling-based bone formation, and the mineralization of that matrix that is independent of the remodeling or modeling activity captured by the remodeling marker.…”