MO568STATIC PARAMETERS OF HISTOMORPHOMETRY FOR THE EVALUATION OF BONE TURNOVER IN RENAL OSTEODYSTROPHY

Background and Aims A full histomorphometric analysis of a transiliac bone biopsy with prior tetracycline labeling remains the gold standard to diagnose renal osteodystrophy. Bone turnover is primarly evaluated by the dynamic parameter bone formation rate, calculated from the incorporation of tetracycline in bone. In cases of failed tetracycline labels, however, an evaluation of bone turnover based on static parameters is warranted. This study investigates the diagnostic accuracy of static histomorphometric parameters for the diagnosis of high and low bone turnover. Method Bone biopsies with prior tetracycline labeling of sufficient quality for a full histomorpometric analysis were included (n = 205). Mean age of participants was 56±13 years, 67% were men, and 22% had diabetes mellitus. Diagnostic accuracy of static histomorphometric parameters for bone turnover was evaluated by area under the receiver operator characteristics curve (AUC) statistics, against the full set of static and dynamic histomorphometric parameters. The cohort was randomly split to allow calculation of optimal diagnostic cutoffs in an exploration cohort (n=105), with subsequent validation in a separate subset of patients (n=100). Results All histomorphometric parameters were significantly different across categories of low (24%), normal (60%), and high (16%) bone turnover (p < 0.01), and all were significant predictors of both high and low bone turnover (Figure 1). Calculated optimal cutoffs and their sensitivities and specificities in the validation cohort are shown in Table 1. Diagnostic accuracy was very good for high turnover, as the combination of presence of fibrosis with ObPm>5.4%, OcPm>1.5%, and OAr>2.4% provided a correct diagnosis in 94% of patients, with positive (PPV) and negative (NPV) predictive values of 80% and 96%, respectively. Using the same predefined combination, an accuracy of 80% was achieved for low turnover (no fibrosis, ObPm≤1.9% OcPm≤0.9% and OAr≤1.6%), with a PPV of 71% and a NPV of 82%. Conclusion Static histomorphometric parameters provide an acceptable alternative for the diagnosis of high and low bone turnover. In the absence of successful tetracycline labeling, the proposed cutoffs may provide a suitable alternative for the evaluation of bone turnover in renal osteodystrophy.

Prospective Evaluation of the Bone Anabolic Effect of Bortezomib in Relapsed Multiple Myeloma (MM) Patients.

Bortezomib (B) has been shown to increase osteoblast activity and inhibit osteoclast formation, thus promoting bone formation. We have previously reported a correlation between increased alkaline phosphatase (ALP) and the response to B in patients with MM. We now report results of a detailed prospective study examining the skeletal effects of B treatment in MM patients using histomorphometry, micro computed tomography (microCT) and markers of bone metabolism. Methods: Single agent B (1.3 mg/m2 patients 1–10; 1mg/m2 patient 11–20), was administered on days 1, 4, 8 and 11 on a 21 day intervals for a total of 3 cycles; no patients were receiving concurrent bisphosphonates or steroids during the entire study period. The dynamic indices of bone turnover were prospectively evaluated via tetracycline labeling prior to transiliac bone biopsies obtained at baseline and after 3 cycles of treatment. Biopsy specimens were examined by high-resolution microCT prior to histomorphometric analyses. Architectural parameters such as bone volume/total volume (BVTV), trabecular number (TbN), and thickness (Tb.Th) were recorded. Osteocalcin, and alkaline phosphatase on days 1,4,8,11 were measured before and after each B dose and every 4 hours thereafter, daily for the other days of the treatment cycle. Results: Histomorphometric analyses were compared in 7 of the 11 patients who completed the trial. All 11 patients underwent bone biopsy at baseline nine of those 11 at the end of the study (2 samples were not adequate). Baseline BV/TV values ranged from 13% to 80%. After 3 cycles of B treatment % increase (mean 37%) in BV/TV was shown in 6 of 7 patients (P<0.034). Tb.Th was also increased from baseline (range 20%–456%) in 5 of 7 patients (71%) who responded to B. Histological bone histomorphometry demonstrated a lack of osteoid formation and osteoblast activity at baseline and a marked increased in osteoid and osteoblast numbers on trabecular and cortical bone surface following B treatment. Tetracycline incorporation into bone was observed in only 2 of 11 of patients (18%) at baseline, reflecting the extremely low levels of bone turnover in MM patients prior to treatment. However, post-B tetracycline labeling was observed in 7 of 11 (63%) samples (p<0.03; baseline vs post treatment score changes), reflecting the dramatic increases in bone turnover elicited by B treatment. Interestingly, after B treatment, the rate of bone formation was accelerated in the 2 patients with measurable baseline tetracycline labeling. Baseline osteocalcin values were below the reference intervals (11–50 ng/ml) in 10 of 11 patients but increased in 9 of 11 patients at the end of the third B cycle. Overall osteocalcin changes increased from baseline by 403% (p<0.037). BALP ranged from 4.5 to 48.4 ug/l at baseline and increased in 6 of 10 patients following B treatment. Conclusion: In this first prospective single agent B study we demonstrate that even a short course (3 cycles or 12 doses) of B treatment has a significant and potent anabolic bone effect in MM patients, demonstrated by serum turnover markers, micro-CT measures of bone architecture and by static and dynamic histomorphometry.

Bone Remodeling in Immediately Loaded and Unloaded Titanium Dental Implants: A Histologic and Histomorphometric Study in Humans

Remodeling is thought to prevent microdamage accumulation caused by repetitive loading and to increase the fatigue life of bone. The bone remodeling rate (BRR) is the period of time needed for new bone to replace the existing bone and to allow for the adaptation of bone to its environment. BRR is expressed as a percentage or volume of new bone within a specific time period. The aim of the present study was to evaluate bone remodeling events on submerged and immediately loaded dental implants. Twelve patients with edentulous mandibles participated in this study. All patients were rehabilitated with fixed mandibular prostheses, with 10 dental implants per patient. An additional implant was inserted in the most distal posterior mandibular jaw region. In 6 patients, these additional implants were loaded with a fixed provisional prosthesis the same day of the implant surgery and loaded. In the other 6 patients, the additional implants were left submerged and not loaded. After 6 months, all the additional implants were retrieved with a trephine. The percentage of woven and lamellar bone, number of osteoclasts and osteoblasts, and percentage of bone labeled by tetracycline at 0.5 mm and 2 mm from the implant surface were evaluated. The percentage of lamellar bone, number of osteoblasts, and percentage of bone tetracycline labeling was significantly higher in the loaded implants than in the unloaded implants (P = .0001). Also in the loaded implants, the percentage of woven and lamellar bone, number of osteoclasts and osteoblasts, and percentage of bone tetracycline labeling was significantly higher at 0.5 mm than at 2 mm from the implant surface (P = .0001). No such differences were found in unloaded implants (P = .377). In conclusion, we found that (1) loading appeared to stimulate bone remodeling at the interface, (2) a higher percentage of lamellar bone was found in loaded implants, (3) the percentage of bone labeling was higher at the interface of loaded implants, (4) no differences were found in the BRRs between immediately loaded and unloaded implants, and (5) immediate loading had not interfered on the lamellar bone formation at the interface and had not produced formation of woven bone at the interface.