Local treatment of cancellous bone grafts with BMP-7 and zoledronate increases both the bone formation rate and bone density

Figures & data

Figure 1. A. The bone conduction chamber with a freeze-dried graft. The graft is placed in the chamber and mesenchymal tissue grows in from the bottom upwards into the bone graft, which subsequently remodels. B. Histological picture (hematoxylin and eosin, ×20) of an untreated graft after 6 weeks in the chamber. Ingrowth occurs from the bottom of the picture as the graft is revascularized. Bone formation lags behind the vascular ingrowth and starts with an osteoclastic resorption of the bone graft, followed by a front of new forming bone. In this unloaded model, the new bone is almost entirely resorbed and finally remodeled into a fatty cell marrow.

Figure 2. Histological specimens representing the 4 treatment groups after 6 weeks in the chamber (hematoxylin and eosin). Host tissue enters the graft through holes in the bottom of the chamber and ingrowth/remodeling occurs from the bottom upwards. The front of bone ingrowth is marked with a black line. A. Saline-treated chamber specimen with remodeled bone graft below the arrows. Most of the newly formed bone below the bone ingrowth front has already been remodeled into a fatty cell marrow. B. In the BMP-7-treated specimens, the bone ingrowth front has reached further into the graft than in the controls. C. In the zoledronate-treated specimens, the remodeled bone below the ingrowth front has a BV/TV (bone volume/total volume) value about 3 times higher than in the controls. D. Here, both BMP-7 and zoledronate were given and both the ingrowth distance and bone retention are increased compared to the control. The images have been chosen to be representative of the group median in terms of bone ingrowth and BV/TV value.

Table 1. The catabolic part of the bone remodeling, illustrated by the BV/TV value (bone volume/total volume; expressed as median (range)). BV/TV is mainly influenced by the addition of a bisphosphonate, which stalls catabolism. Comparisons are shown unpaired between the right sides, treated with BMP-7 and the left sides, treated with saline, for both the zoledronate (ZA) group and the control group. The amount of new-formed bone on the old graft is given for comparison

	Saline(n = 17)	ZA(n = 15)	p-value	BMP-7(n = 15)	BMP-7 + ZA(n = 16)	p-value
BV/TV, %	16 (10–40)	56 (37–68)	< 0.001	14 (2–54)	50 (40–57) ^a	< 0.001
New-formed	14 (7–34)	47 (23–58)		11 (2–43)	39 (26–56)
Retained graft	2 (0–12)	11 (5–17)		2 (0–10)	11 (7–18)

^a p < 0.001 vs. control.

Table 2. The anabolic part of the bone remodeling, illustrated by the bone ingrowth distance of new bone into the chamber (median (range)). Bone ingrowth distance is mainly influenced by the addition of a bone proliferation and differentiation inducer such as BMP-7. Comparisons have been made pairwise (15 complete pairs) between the right side, treated with BMP-7, and the left side, treated with saline, for both the zoledronate (ZA) group and the control group

	Saline	BMP-7	p-value	ZA	ZA + BMP-7	p-value
Ingrowth, mm	2.6 (1.5–4.4)	3.0 (1.9–4.4)	0.07	2.3 (1.0–3.5)	3.5 (2.4–5.8) ^a	< 0.003

^a p = 0.002 vs. control.

Figure 3. Bisphosphonate-treated specimen to the left (A) and saline-treated control to the right (B) (hematoxylin and eosin, ×40). A. Note how the new-formed bone (NB), identifiable by the existing cell nuclei (black arrows), covers the old graft bone (G) with its lost nuclei (white arrows). Due to the delayed resorption, an old bone–new bone construct is formed. B. In the saline-treated control, such a construct does not form as extensively. The graft bone (G) is resorbed and replaced by new bone (NB), which is in turn immediately resorbed, being replaced by a hematogenous/fat cell marrow (Ma).