Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?

Bisphosphonates are considered the most effective drugs for controlling adult and pediatric osteolytic diseases. Although they have been used successfully for many years, several side effects, such as osteonecrosis of the jaw, delayed dental eruption, atypical femoral fracture, and alterations to the bone growth system, have been described. After an overview of nitrogenous bisphosphonate, the purpose of this article is to describe their mechanisms of action and current applications, review the preclinical and clinical evidence of their side effects in the skeleton ("what we know"), and describe current recommendations for preventing and managing these effects ("what we can do"). Finally, promising future directions on how to limit the occurrence of these side effects will be presented.

Nasal changes with nasoalveolar molding in Colombian patients with unilateral cleft lip and palate.

PURPOSE: Presurgical nasoalveolar molding (PNAM) is controversial in maxillofacial orthopedics. It supposedly improves the nasal esthetics and function in unilateral cleft lip/palate (UCLP) patients. However, there is no research available in South America to support this claim. The purpose of this study was to evaluate the efficacy of presurgical nasoalveolar molding therapy on morphological changes of the noses of unilateral cleft lip/palate patients in a Colombian sample. METHODS: Seventeen neonate UCLP patients using PNAM received facial impressions at the beginning of treatment; before primary rhinocheiloplasty; and before palatoplasty. A submentovertex photograph of each cast was taken and analyzed by digital photogrammetry. Wilcoxon and Friedman tests were used for within- and between-group comparisons. RESULTS: A statistically significant reduction of cleft nostril width, without significant changes in noncleft nostril width or total nasal width, was found after PNAM. A significant increase in cleft and noncleft nostril height, plus a nonsignificant increase in nostril area in both sides and a nonsignificant uprighting of the columella were found. These changes were maintained or further improved after rhinocheiloplasty. CONCLUSION: The presurgical nasoalveolar molding technique improved nasal tip projection and alar cartilage depression and decreased partially columella deviation before rhinocheiloplasty in South American unilateral cleft lip/palate patients.

Nasal changes after presurgical nasoalveolar molding (PNAM) in the unilateral cleft lip nose.

PURPOSE: Nasal reconstruction for patients with unilateral cleft lip and palate (UCLP) is a challenge for the reconstructive surgeon. Presurgical nasoalveolar molding (PNAM) was introduced to reshape the cleft nasal structures prior to lip repair. This study analyzed two-dimensional nasal changes before and after PNAM in patients with complete UCLP. METHODS: Thirty UCLP patients (19 males; 11 females) who received PNAM before lip repair were included in this study. PNAM was applied for 100 days. Nasal casts were obtained before and after PNAM. Frontal and 45° standardized digital photographs were taken from all casts, and a photogrammetric analysis (16 linear, six angular, and two area measurements) was performed. Paired Student's t tests were used to search for differences by time, and time versus side (cleft versus noncleft). RESULTS: Significant reduction of cleft columella deviation with an increase in columella length, nostril height, and axial inclination on the cleft side were recorded. This resulted in an increase in the projection of the nasal tip. The noncleft measurements remained without significant changes. The cleft nostril area increased significantly more than the noncleft side by 90% with PNAM treatment. Significant normal growth changes were observed in nasal width and nasal height. CONCLUSION: A favorable reshaping of the nose after PNAM was achieved, resulting in an improvement in form before lip surgery. These changes lead to improved nasal symmetry before primary lip and nasal reconstruction in UCLP patients.

Histological evaluation of the temporomandibular joint after bilateral vertical ramus mandibular distraction in a canine model.

The aim of this pilot study was to histologically evaluate the effect of bilateral vertical mandibular distraction osteogenesis (DO) on the temporomandibular joint (TMJ) in a canine model. Eight male beagle dogs underwent DO, with the placement of single-vector internal distractors. One unoperated animal served as control. After a latency period of 7 days, distraction was performed at a rate of 1 mm a day for an average of 12 days. The animals were divided into two groups (n = 4) and sacrificed after one or two months of consolidation. Eighteen TMJs were prepared for histological evaluation. Control TMJs surfaces were smooth, with no irregularities and trabecular bone was thick and multiply connected. In the one-month group, thinning of the trabecular bone was evident. The trabeculae were long, not multiply connected, parallel to each other and perpendicular to the articular surface. Although overall fibrous-cartilaginous tissues covering the TMJs were maintained with no signs of degenerative changes, one condyle from the one-month group had depressions and erosions of the fibro-cartilage layer and subcortical bone. In the two-month group, overall bone and cartilage architecture was more similar to the control specimens. This study indicates that, in the short term, gross changes can occur in the TMJ after bilateral mandibular vertical ramus distraction. These changes seem to be a process of biological adaptation to the pressure and functional changes secondary to surgery and distraction. However, long-term studies are needed to confirm whether the changes are completely reversible.

Micro-computed tomography evaluation of the glenoid fossa and mandibular condyle bone after bilateral vertical ramus mandibular distraction in a canine model.

The aim of this study was to quantify bone microarchitecture within the glenoid fossa and mandibular condyle following mandibular distraction osteogenesis. Eight 6- to 9-month-old male beagle dogs underwent bilateral vertical mandibular distraction with semiburied distractors (12 days of distraction at 1 mm per day). One unoperated animal served as control. After distraction the animals were divided into two groups (N = 4) and killed after 1 or 2 months of consolidation. Three-dimensional trabecular architecture was analyzed by micro-computed tomography (microCT). At both sites the overall trends were similar. In the glenoid fossa, there was decreased bone volume, trabecular number, and connectivity density and increased trabecular separation at 1 month and decreased trabecular thickness and increased structure model index compared with the control (P < 0.05). In the mandibular condyle, there was decreased bone volume, trabecular number, and connectivity density at both 1 and 2 months, with decreased trabecular thickness and increased structure model index at 2 months only compared with the control (P < 0.05). The bone became less dense and more rodlike. These bone changes are similar to those seen by the effects of aging or impaired normal function. Thus, in the short term, changes occur in the bone microstructure of the glenoid fossa and mandibular condyle after vertical mandibular ramus distraction in the canine model.

Micro-computed tomography evaluation of the glenoid fossa and mandibular condyle bone after bilateral vertical ramus mandibular distraction in a canine model.

The aim of this study was to quantify bone microarchitecture within the glenoid fossa and mandibular condyle following mandibular distraction osteogenesis. Eight 6- to 9-month-old male beagle dogs underwent bilateral vertical mandibular distraction with semiburied distractors (12 days of distraction at 1 mm per day). One unoperated animal served as control. After distraction the animals were divided into two groups (N = 4) and killed after 1 or 2 months of consolidation. Three-dimensional trabecular architecture was analyzed by micro-computed tomography (muCT). At both sites the overall trends were similar. In the glenoid fossa, there was decreased bone volume, trabecular number, and connectivity density and increased trabecular separation at 1 month and decreased trabecular thickness and increased structure model index compared with the control (P < 0.05). In the mandibular condyle, there was decreased bone volume, trabecular number, and connectivity density at both 1 and 2 months, with decreased trabecular thickness and increased structure model index at 2 months only compared with the control (P < 0.05). The bone became less dense and more rodlike. These bone changes are similar to those seen by the effects of aging or impaired normal function. Thus, in the short term, changes occur in the bone microstructure of the glenoid fossa and mandibular condyle after vertical mandibular ramus distraction in the canine model.

Microstructural and strength evaluation of regenerate tissue during the consolidation period after vertical mandibular ramus distraction.

Mandibular ramus height restoration by distraction osteogenesis (DO) is a key procedure in mandibular hypoplasia reconstruction. The objective of this study was to evaluate short-term skeletal changes in the regenerated bone after vertical mandibular ramus DO using a buried distraction device. Eight subadult beagle dogs underwent bilateral vertical mandibular ramus DO. After a 7-day latency period, distraction was performed at a rate of 0.5 mm twice a day for 12 days. Four dogs were killed at 1 month and four dogs at 2 months after the end of distraction. One intact beagle was included as an unoperated control. After sacrifice, micro computed tomography (muCT) and mechanical testing of distracted sites were used to measure bone volume (BV), total volume (TV), and mechanical peak load strength, respectively. The muCT images showed wide variation in the response, with some animals demonstrating considerable bone formation and reconstitution of the canal for the inferior alveolar nerve. Quantitatively, BV was no more than 67% and BV/TV was less than 25% of the intact control, and strength was approximately 33% of the intact control value. The 1 and 2 month values were similar. These results suggest that internal distractors can successfully reconstitute bone but that the regenerated tissue did not regain structural and mechanical characteristics of native bone within the 2 month study period.