BoneKEy-Osteovision | Commentary

Recent contributions of iliac bone histomorphometry to understanding the anabolic effect of parathyroid hormone



DOI:10.1138/2002017

Parathyroid hormone (PTH) is the most promising new treatment for osteoporosis () and the mechanism of its anabolic action is receiving much attention. Suggestions for the origin of the additional osteoblasts include increased proliferation of the usual osteoblast precursors (), recovery by lining cells of the capacity to synthesize bone matrix (), and delayed apoptosis of existing osteoblasts (). In birds given estrogen lining cells can revert to an even earlier, proliferative stage in their lineage (), and it is conceivable that the same could happen in response to PTH. None of these possibilities has been conclusively ruled out, but none is likely to be solely responsible, and their relative importance awaits further studies.

At the recent ASBMR meeting in Phoenix, David Dempster presented histologic findings after 28 days treatment in 27 postmenopausal osteoporotic women (). Compared to untreated age and sex matched patients with osteoporosis, tetracycline based bone formation rate was increased on the periosteal (Ps) and endocortical (Ec) surfaces of the cortex as well as on the cancellous (Cn) surface. This is the first time that such a global response has been demonstrated. At forming sites present before treatment on the Ec surface, the formation period was prolonged, a result expected from delayed apoptosis. On the Cn surface the effect was more complex. Beneath some bone forming sites the cement line was not scalloped but smooth, from which the authors inferred that some regions of quiescent surface had transformed directly to formation without intervening resorption, a process that would necessarily involve lining cells in some way. But if there are more osteoblasts than are needed to refill the cavity, for whatever reason, they could spill over onto adjacent quiescent surfaces, a possibility first suggested for sodium fluoride treatment (). More evidence is needed to establish conclusively that PTH can induce bone formation to begin on the quiescent surface, rather than simply encroach on it.

In the October 2001 issue of the Journal of Bone and Mineral Research, the same group of investigators reported the histologic changes after PTH treatment for 18 months in eight men and 36 months in 8 women (). Ordinary histomorphometry showed no significant changes in cancellous bone in either group except for a 10% increase in wall width in men, but micro CT showed a suggestive trend to an increase in connectivity density. The mean value was increased by 20% in men and 40% in women, which did not reach conventional significance; however, in 2 of 8 men and 1 of 6 women, the posttreatment values were above the 95% confidence limit derived from the pretreatment values.

Connectivity density is a tricky concept, since an increase is not necessarily beneficial nor a decrease necessarily harmful! Perforation of a trabecular plate, as occurs in the early stages of estrogen deficiency, will increase connectivity density because the number of topologically distinct pathways in 3 dimensions will increase (). If the perforation could be closed, connectivity density would go down because the number of distinct pathways would decrease. But after the plates have been transformed to rods, transection of a rod will decrease connectivity density, and reconnecting the broken ends will increase it. It is confusing that the same directional change in a measurement can signify either deterioration or improvement in architecture, depending on the initial condition. The subjects of the study were fairly young (mean age 49 in the men and 54 in the women), but their condition was probably sufficiently advanced that an increase in connectivity density would have been beneficial rather than harmful.

The most striking finding in this study was a significant increase in iliac cortical thickness in the women of 319 µm measured directly (n = 8) and 351 µm measured by micro CT (n=6). Because Iliac biopsy cores may be taken obliquely, direct measurement of cortical thickness may be too high, but only by 4/π or 1.27 (). Even the smallest of these figures represents an average increase of 0.229 µm/d for three years. There was no significant increase in core width (Dempster, personal communication) and it was not possible to decide how the increase was divided between the periosteal and endocortical surfaces, but assuming an equal division there would have to have been a net bone formation rate (BFR) of at least 42 µm3/µm2/y on both sides. The cancellous BFR at the time of the second biopsy was 21 µm3/µm2/y, compared to mean values of 16.4 before treatment and 15.3 in healthy postmenopausal women (). On the periosteal and cortical surfaces BFR was not different from the pretreatment values. Obviously BFR had been much higher earlier in the course of treatment, but the stimulatory effect of PTH had largely subsided by the time of the second biopsy.

Bone formation rate can be partitioned into two components: activation frequency, which is the probability that a new episode of bone formation will begin on any element of surface, and wall thickness, which is the amount of new bone that will be made during each episode (), a relationship expressed as:

BFR (µm3/µm2/y) = Ac.f(/y)*W.Th(µm).

A large increase in BFR, as was demonstrated soon after PTH administration () and inferred during the early course of prolonged treatment (), is always mainly due to an increase in Ac.f. It makes no difference to this conclusion whether a particular episode of bone formation was or was not preceded in the usual way by bone resorption. Increases in Ac.f and W.Th both depend on increases in osteoblast production, but the former reflects the number of new osteoblast teams, each representing one new bone forming project, and the latter the number of osteoblasts in each team, an index of how much effort is put into each project. The data in the current study are incomplete, but the persistent increases in wall thickness alone in men and in activation frequent alone in women suggest that the decision to begin a new bone formation project at a particular location and the decision of how many cells to deploy in executing the project can be made independently.

Whether or not the reader chooses to interpret the findings in terms of this model, it remains unarguable that the anabolic effect of PTH subsided in strength with time, and it is obviously important to elucidate the reason(s) for this diminishing response. Although the treatment was intermittent in the sense that a single injection of PTH increases the circulating level for only a few hours (), it was continuous in the sense that the injections were given daily for prolonged periods. One obvious strategy is to give much shorter courses of treatment, which would be intermittently intermittent rather than continuously intermittent! The means are now at hand to explore this and other strategies both in appropriate animals models () and in human subjects ().


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