A10 Abstracts from Bone Morphology 1992, Lexington, Kentucky

37 BONE HISTOLOGY DURING POST-LIVER TRANSPLANT BONE LOSS. DUNSTAN CR, SOMERS NM, MCCAUGHAN GW, STRASSER S, EVANS RA. METABOLIC UNIT, CONCORD HOSPITAL AND A.W. MORROW GASTROENTEROLOGY AND LIVER CENTRE, ROYAL PRINCE ALFRED HOSPITAL; SYDNEY, AUSTRALIA We have previously shown that orthotopic liver transplant (OLT) was associated with a 24% reduction in spinal bone mass occurring over three months. No further bone loss occurred over the following 9 months. Bone biopsies taken at three months showed increased bone formation, but no change in osteoclast surfaces (1). Subsequently, we found urinary calcium excretion to reach a a maximum at 5-6 weeks after OLT. This study was carried out to determine the histological changes occurring at 6 weeks post-transplant while rapid bone loss was apparently still occurring. In I1 patients, spinal bone mass was measured and bone biopsies were taken from the posterior ileum following double tetracycline labelling before and 6 weeks after liver transplantation. Three consecutive sections were cut. Section 1 was reacted for acid phosphatase and counterstained with orange G and light green to show osteoclasts, osteoid and mineral&d bone. Section 2 was stained with pyronin to demonstrate osteoblasts. Section 3 was viewed unstained for tetracycline labels. The bone was measured using colour based automated image analysis for bone density, osteoid and osteoclast variables and a semi-automated analysis for osteoblasts and tetracycline labelling. Histological changes were very variable, ranging from decreased bone formation relative to resorption in 6, no change in 2, and increased formation relative to resorption in 3. Pretransplant and post-transplant levels were 3.6k3.0 and 2.2~1.8 (NS) for osteoid surface, 1.4+1.1 and 1.1-+1.6 (NSJ for osteoblast surface, and 0.8+0.8 and 1.0+0.7 (NS) for osteoclasts/mm tissue area. Change in no histological variable correlated with the decrease in bone mineral density in the spine (12~1 I%, p<O.O05). The variable histological responses to OLT do not clearly explain the loss of bone which occurs in the spine. The variable response may reflect heterogeneity in bone, changes in resorption velocity (not measurable), or some patients may have been losing bone prior to OLT. A larger series of patients is required to resolve these issues. 1. McDonald IA er al Bone loss after liver transplantation. Hepatology 1991;14:613619.

39 CANCELLOUS BONE REMODELING IN MEDULLARY THYROID CARCINOMA. EF Eriksen, H. Kudsk. K. Emmertsen. P.Charles. L. Mosekilde, F. Melsen. Aarhus Bone and Mineral Research Group, University Departments of Endocrinology and Pathology, Aarhus Amtssygehzu.

Calcitonin acts as an antiresorptive agent in pharmacologic doses, and is used for the treatment of osteoporosis. The actual effects on resorptive and formative bone cell populations are, however, not well characterized. In order to assess the influence of chronic calcitonin excess on cancellous bone remodeling we studied the remodeling sequence in 10 patients with medullary thyroid carcinoma (MTC) (4 females and 6 males, mean age 51 years) and compared the results to reconstructed sequences obtained in 10 normal age- and sex- matched controls (5 females and 5 males, mean age 46 years).

The reconstruction of the remodeling sequence was based on the method of Eriksen et al. and was performed on iliac crest bone biopsies obtained after intravital tetracycline double labeling with a labeling interval of 10 days.

The two groups exhibited similar erosion periods (44 vs 37 days in controls), erosion rates (3.5? 1.9 vs. 5.5e2.8 pm/day) and no difference in final erosion depth was demonstrable (49.0? 6.9 vs. 51.228.4 pm in controls). The formative periods were not significantly different (178 vs. 116 days), and the two groups exhibited similar values for MAR (0.61+0.13 vs. 0.64?0.10 pm/day). A trend towards increased mean wall thickness in MTC was evident (5 1.4 2 4.0 vs. 47.6?4.2 pm (p=O.O54), and this resulted in a more positive balance in MTC (2.429.4 in MTC vs. -3.427.7 pm in controls (N.S.). Mineralization lag time was the same in the two groups and no difference in activation frequency was demonstrable (0.47 in MTC vs 0.69 year-‘).

In conclusion, no significant aberrations in bone remodeling of MTC patients was demonstrable in this study. The remarkable trend towards increased W.Th and positive balance needs to be validated in larger materials.

38 EROSION DEPTH ASSESSED BY LAMELLAR COUNTING. Erik Eriksen. Aarhus Bone and Mineral Research Group, University De artment of Endocrinology and Pathology, Aarhus Amtssygehus, f3K-8000, Aarhus C., Denmark.

Courpron et al. (1981) devised the first method for the indirect estimation of erosion depth (E.De) by relating mean thickness of interstitial bone to mean trabecular thickness. It has recently been employed by Croucher et al. (1989). The method is rather insensitive, when it comes to assessment of short term changes in bone resorption, because the thickness estimates are infhrenced by remodeling that took place before the change of interest occurred.

A more sensitive method, which only measures ongoing resorption, is based on counting the number of lamellae eroded in oolarized lieht (Eriksen et al. 1984). Bv relatine E.De to cell tvoe ihe whole resorption sequence can be reconst?ttcted. Based’& E.De and tetracycline based calculations of function periods, resorption rate can be calculated by the BMU- and tissue level.

The method can be performed without any use of digitizing or image-processing devices, and is therefore very rapid. The maximal reproducibility (8%) is reached by counting a total of 25 intersections equally divided over 4 sections cut at 100 pm intervals.

Resorption rates calculated by this method have been found to correlate significantly to resorption rates assessed by calcium kinetics (Charles et al. 1987), biochemical markers of bone resorption (Eriksen et al. 1991, Kotowicz et al. 1992) and PHI levels in osteoporosis (Kotowicz et al. 1990).

40 PREVENTIVE EFFECTS OF THE NEW BISPHOSPHONATE, BM21.0955, ON THE BONE LOSS OCCURRING AFTER CESSATION OF OVARIAN FUNCTION IN EXPEIUMENTAL DOGS. M.C. Faueere, F. Bauss, RM. Friedler, and H.H. Malluche, Div. Nephrology, Bone & Mineral Metab., U. of Kentucky, Lexington, KY and Boehringer-Mannheim, Germany.

We reported that bone loss occurs as soon as 1 month after ovariohysterectomy (OHX) in dogs (JBMR, 1990, 5:263-72). However, only indirect si

Z! ns of increased bone resorption were

found. To further eluct ate this observation and evaluate the effects of a new bisphosphonate, BM21.0955 (BM21) do s underwent OHX (n=36) or sham operation (SHAM, n=12 . ‘i OHX dogs were divided into 6 groups (n=6 each) and received vehicle (Veh) or BM21 at various doses (0.1, 0.3, 1, 10 and 100 pg/kg/d) for 1 month. SHAM dogs were given Veh (n=6) or BM21 (1 pg/kg/d, n=6). Iliac crest bio were done at baseline and at month 1. 8

sies and blood drawings o changes were observed

in the SHAM animals. Relevant results in the OHX dogs are shown below expressed as % of baseline values:

DOSE (w/kg/day)

.OO .I0 .30 1.00 10.00 100.00

1.25 0 -29.It 7.ha -49.5t 7.2' 5.5t 0.7 5.0t14.5 0.6il3.3 0.ot12.1

W/T" -1O.h 3.0a -2b.t.f 5.~3~ -30.8t 4.Qa -7.Ot 4.6 2.7t 8.4 -1.3* 6.5

E.Oe. 23.4i15.3a 2.9t 9.8 -0.6t13.7 5.8il5.4 4.4t14.4 -lP.O* 6.5

llAR -2.6e16.2 4.825.2 -23.a 4.2 -9.9t21.4 -31.5t19.5 -1l.h 6.0

IWBS -4.bi23.7 6.0t0.7 16.Qtl6.0 -36.lt21.3 -82.52 4.qa -83.Ot 3.3a

a p<O.OS different frm baseline

W/TV: Bone Volune/Tissue Volume E.Oe.: Erosion Depth

MAR: Mineralization Apposition Rate MSILIS: Mineralizing Surface

The increase in erosion depth in OHX dogs given Veh indicates that indeed a dramatic increase in osteoclastic activity occurs early after ovariohysterectom this increase and maintains i(

. BM21 at a dose ‘1 pg/kg prevents one volume. No osteomalacia was

observed at any dose of BM21. At a dose 10 pg/kg, BM21 inhibits bone turnover which is not seen at a dose of 1 pg/g. The mechanisms of action of BM21 on 1,25 D metabolism are unclear. BM21 apparently represents a potent antiresorptive agent with a relatively wide therapeutic margin.