Strategies for stimulation of new bone formation: a critical review.

Large bone defects, congenital or caused by diseases, trauma or surgery, do not heal spontaneously and are usually a clinical challenge in the orthopedic and dental practices. A critical review concerning strategies to substitute lost bone or stimulate osteogenesis was undertaken. Pivotal concepts ranging from traditional bone grafting and use of biomaterials to local application of growth factors and gene therapy were addressed, including critical comments on the efficacy and safety, difficulties, advantages and disadvantages of each method. The most predictable results are still obtained with autogenous bone graft, despite the inconveniences of morbidity and limited availability of graft material. Satisfactory results have been reported for recombinant bone morphogenetic proteins (rhBMPs)-2 and -7, which distinguish for their osteoinductive property, the difficulty being the need for a degradable carrier that allows its continuous release in a rate compatible to that of new bone formation. Other bone growth factors are currently under evaluation in preclinical models of bone defects; however their efficacy is also dependent on the competence of a delivery strategy and on an appropriate delineation of "which one", "which dose" and "when". Parameters of efficiency and safety for gene therapy are still being established. In conclusion, given the variety of growth factors involved in the complex cascade of bone repair and the biological interactions between them, it remains a challenge to accomplish the ideal strategy to stimulate reparational bone formation in specific conditions of the medical as in the dental practices.

Histometric study of alveolar bone healing in rats treated with the nonsteroidal anti-inflammatory drug nimesulide.

PURPOSE: There is extensive experimental and clinical evidence in the orthopedic area that prolonged use of nonselective (inhibitor of both cyclooxygenases 1 and 2) nonsteroidal anti-inflammatory drugs can hinder long bone fracture healing, spinal fusion rate, and new bone formation around implants. The purpose of the present study was to investigate whether nimesulide (Nimesulida, Medley S.A., Campinas, SP, Brazil), a preferential cyclooxygenase-2 inhibitor, can hinder alveolar bone healing, in rats. MATERIALS AND METHODS: Treated rats received oral doses (5 mg/kg/rat/day) of nimesulide from the day of tooth extraction until euthanasia 2 weeks later and control rats received tap water (n = 5 per group). The volume of neoformed bone inside the alveolar socket was estimated in semiserial longitudinal histological sections by a differential point-counting method, and the significance of the difference between groups was analyzed by Student t test (P < 0.05 for statistical significance). RESULTS: Histometric data confirmed histological observation that the volume fraction of new bone trabeculae in treated rats was not significantly different from that in control rats. CONCLUSION: Short-term treatment with nimesulide, although its capacity to inhibit preferentially the enzyme cyclooxygenase-2, does not interfere with alveolar bone healing in rats.

Strategies for stimulation of new bone formation: a critical review

Large bone defects, congenital or caused by diseases, trauma or surgery, do not heal spontaneously and are usually a clinical challenge in the orthopedic and dental practices. A critical review concerning strategies to substitute lost bone or stimulate osteogenesis was undertaken. Pivotal concepts ranging from traditional bone grafting and use of biomaterials to local application of growth factors and gene therapy were addressed, including critical comments on the efficacy and safety, difficulties, advantages and disadvantages of each method. The most predictable results are still obtained with autogenous bone graft, despite the inconveniences of morbidity and limited availability of graft material. Satisfactory results have been reported for recombinant bone morphogenetic proteins (rhBMPs)-2 and -7, which distinguish for their osteoinductive property, the difficulty being the need for a degradable carrier that allows its continuous release in a rate compatible to that of new bone formation. Other bone growth factors are currently under evaluation in preclinical models of bone defects; however their efficacy is also dependent on the competence of a delivery strategy and on an appropriate delineation of “which one”, “which dose” and “when”. Parameters of efficiency and safety for gene therapy are still being established. In conclusion, given the variety of growth factors involved in the complex cascade of bone repair and the biological interactions between them, it remains a challenge to accomplish the ideal strategy to stimulate reparational bone formation in specific conditions of the medical as in the dental practices.

Defeitos ósseos de grandes dimensões, congênitos ou causados por doenças, traumas ou cirurgias, não se regeneram espontaneamente e são, no geral, um desafio para médicos e dentistas. O presente trabalho apresenta uma revisão crítica sobre estratégias para substituir tecido ósseo ou estimular a osteogênese reparacional. São apresentados conceitos relevantes relativos aos métodos tradicionais de enxertos/implantes ósseos e uso de biomateriais até a aplicação local de fatores de crescimento e a terapia gênica, incluindo comentários críticos sobre eficácia, segurança, dificuldades, vantagens e desvantagens de cada método. Os resultados mais previsíveis ainda são obtidos com enxertos ósseos autógenos, apesar das incoveniências de morbidade e disponibilidade limitada de material. Resultados satisfatórios têm sido relatados com o uso de proteínas ósseas morfogenéticas humanas recombinantes (rhBMPs)-2 e -7, que se distinguem pela capacidade de osteoindução, apesar da necessidade do uso combinado com um carreador biodegradável que permita sua liberação em um ritmo compatível com o da neoformação óssea. Outros fatores de crescimento ósseo estão presentemente em fase pré-clinica de avaliação e sua eficácia também depende de uma estratégia adequada de liberação, além da definição de parâmetros como “qual fator”, “em que dose” e “quando”. Ainda estão sendo estabelecidos os parâmetros de eficiência e segurança para aplicação da terapia gênica em defeitos ósseos. Concluindo, diante da grande variedade de fatores de crescimento envolvidos na complexa cascata do reparo ósseo e das interações que eles estabelecem, definir a melhor estratégia para estimular a formação óssea em situações específicas das práticas médica e odontológica permanece um desafio para cientistas e clínicos.

Treatment with paracetamol, ketorolac or etoricoxib did not hinder alveolar bone healing: a histometric study in rats

Prostaglandins control osteoblastic and osteoclastic function under physiological or pathological conditions and are important modulators of the bone healing process. The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and consequently prostaglandins synthesis. Experimental and clinical evidence has indicated a risk for reparative bone formation related to the use of non-selective (COX-1 and COX-2) and COX-2 selective NSAIDs. Ketorolac is a non-selective NSAID which, at low doses, has a preferential COX-1 inhibitory effect and etoricoxib is a new selective COX-2 inhibitor. Although literature data have suggested that ketorolac can interfere negatively with long bone fracture healing, there seems to be no study associating etoricoxib with reparative bone formation. Paracetamol/acetaminophen, one of the first choices for pain control in clinical dentistry, has been considered a weak anti-inflammatory drug, although supposedly capable of inhibiting COX-2 activity in inflammatory sites. OBJECTIVE: The purpose of the present study was to investigate whether paracetamol, ketorolac and etoricoxib can hinder alveolar bone formation, taking the filling of rat extraction socket with newly formed bone as experimental model. MATERIAL AND METHODS: The degree of new bone formation inside the alveolar socket was estimated two weeks after tooth extraction by a differential point-counting method, using an optical microscopy with a digital camera for image capture and histometry software. Differences between groups were analyzed by ANOVA after confirming a normal distribution of sample data. RESULTS AND CONCLUSIONS: Histometric results confirmed that none of the tested drugs had a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket.

Cola beverage consumption delays alveolar bone healing: a histometric study in rats.

Epidemiological studies have suggested that cola beverage consumption may affect bone metabolism and increase bone fracture risk. Experimental evidence linking cola beverage consumption to deleterious effects on bone is lacking. Herein, we investigated whether cola beverage consumption from weaning to early puberty delays the rate of reparative bone formation inside the socket of an extracted tooth in rats. Twenty male Wistar rats received cola beverage (cola group) or tap water (control group) ad libitum from the age of 23 days until tooth extraction at 42 days and euthanasia 2 and 3 weeks later. The neoformed bone volume inside the alveolar socket was estimated in semi-serial longitudinal sections using a quantitative differential point-counting method. Histological examination suggested a decrease in the osteogenic process within the tooth sockets of rats from both cola groups, which had thinner and sparser new bone trabeculae. Histometric data confirmed that alveolar bone healing was significantly delayed in cola-fed rats at three weeks after tooth extraction (ANOVA, p = 0.0006, followed by Tukey's test, p < 0.01). Although the results of studies in rats cannot be extrapolated directly to human clinical dentistry, the present study provides evidence that cola beverage consumption negatively affect maxillary bone formation.

Cola beverage consumption delays alveolar bone healing: a histometric study in rats

Epidemiological studies have suggested that cola beverage consumption may affect bone metabolism and increase bone fracture risk. Experimental evidence linking cola beverage consumption to deleterious effects on bone is lacking. Herein, we investigated whether cola beverage consumption from weaning to early puberty delays the rate of reparative bone formation inside the socket of an extracted tooth in rats. Twenty male Wistar rats received cola beverage (cola group) or tap water (control group) ad libitum from the age of 23 days until tooth extraction at 42 days and euthanasia 2 and 3 weeks later. The neoformed bone volume inside the alveolar socket was estimated in semi-serial longitudinal sections using a quantitative differential point-counting method. Histological examination suggested a decrease in the osteogenic process within the tooth sockets of rats from both cola groups, which had thinner and sparser new bone trabeculae. Histometric data confirmed that alveolar bone healing was significantly delayed in cola-fed rats at three weeks after tooth extraction (ANOVA, p = 0.0006, followed by Tukey's test, p < 0.01). Although the results of studies in rats cannot be extrapolated directly to human clinical dentistry, the present study provides evidence that cola beverage consumption negatively affect maxillary bone formation.

Treatment with paracetamol, ketorolac or etoricoxib did not hinder alveolar bone healing: a histometric study in rats.

UNLABELLED: Prostaglandins control osteoblastic and osteoclastic function under physiological or pathological conditions and are important modulators of the bone healing process. The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and consequently prostaglandins synthesis. Experimental and clinical evidence has indicated a risk for reparative bone formation related to the use of non-selective (COX-1 and COX-2) and COX-2 selective NSAIDs. Ketorolac is a non-selective NSAID which, at low doses, has a preferential COX-1 inhibitory effect and etoricoxib is a new selective COX-2 inhibitor. Although literature data have suggested that ketorolac can interfere negatively with long bone fracture healing, there seems to be no study associating etoricoxib with reparative bone formation. Paracetamol/acetaminophen, one of the first choices for pain control in clinical dentistry, has been considered a weak anti-inflammatory drug, although supposedly capable of inhibiting COX-2 activity in inflammatory sites. OBJECTIVE: The purpose of the present study was to investigate whether paracetamol, ketorolac and etoricoxib can hinder alveolar bone formation, taking the filling of rat extraction socket with newly formed bone as experimental model. MATERIAL AND METHODS: The degree of new bone formation inside the alveolar socket was estimated two weeks after tooth extraction by a differential point-counting method, using an optical microscopy with a digital camera for image capture and histometry software. Differences between groups were analyzed by ANOVA after confirming a normal distribution of sample data. RESULTS AND CONCLUSIONS: Histometric results confirmed that none of the tested drugs had a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket.

Effect of recombinant human bone morphogenetic protein-2 on bone formation in the acute distraction osteogenesis of rat mandibles.

BACKGROUND: Distraction osteogenesis (DO) is a method of producing new bone directly from the osteotomy site by gradual traction of the divided bone fragments. AIM: The purpose of the present study was to evaluate histomorphometrically whether acute DO would constitute a viable alternative to the conventional continuous distraction treatment and also to verify the capacity of a recombinant human BMP (rhBMP-2) associated with monoolein gel to stimulate bone formation in the acute distraction process. MATERIALS AND METHODS: Forty-eight Wistar rats were assigned to three groups: Group 1, treated at a conventional continuous distraction rate (0.5 mm/day), Group 2, treated with acute distraction of 2.5 mm at the time of the surgical procedure, and Group 3, subjected to acute distraction associated with rhBMP-2. The animals from each experimental group were killed at the end of the second or fourth post-operative weeks and the volume fraction of newly formed bone trabeculae was estimated in histological images by a differential point-counting method. RESULTS: The results showed that after 2 and 4 weeks, bone volumes in the rhBMP-2 group were significantly higher than in the other groups (P<0.05), but no significant difference was observed in the volume fraction of newly formed bone between the continuous and acute DO groups. CONCLUSION: In conclusion, the study indicates that rhBMP-2 can enhance the bone formation at acute DO, which may potentially reduce the treatment period and complications related to the distraction procedure.

Prostaglandins and bone: potential risks and benefits related to the use of nonsteroidal anti-inflammatory drugs in clinical dentistry.

In the skeleton, prostaglandins, mainly PGE(2) produced by osteoblasts under COX-2 stimulation, play either a stimulatory or an inhibitory role in bone metabolism, depending on the physiological or pathological conditions. The anabolic effect occurs largely in response to mechanical forces and in bone fracture healing, whereas PGE(2)-mediated resorption contributes significantly to bone loss in inflammatory diseases and in response to prolonged immobilization. Many reports have shown that conventional nonsteroidal anti-inflammatory drugs (NSAIDs) may delay fracture healing and negatively interfere with spinal fusion in both humans and other animals, whereas the alleged inhibitory effects of COX-2-selective NSAIDs still lacks experimental and clinical evidence. Pertaining to clinical dentistry, recent studies have suggested a potential adjuvant role for NSAIDs in periodontal therapy. There are few experimental reports addressing the deleterious effects of conventional NSAIDs on alveolar bone healing; clinical reports, relating mostly to short-term administration of NSAIDs for management of post-extraction edema and pain, are just as rare and have noted no clinically perceptible delay in bone healing. Additional studies are necessary in order to elucidate whether patients who require reparational bone formation can safely receive prolonged treatment with NSAIDs, and which drug types are less harmful.

Comparison of rat bone healing following intra-alveolar grafting with organic or inorganic bovine bone particles

Aim: This study compared, histometrically, the alveolar bone healing after grafting rats extraction socket with particles of organic or inorganic bovine bone. Method: The volume fraction of grafted materials and bone trabeculae was estimated in histologic images at the end of the 2nd and 9th weeks post-operatively by a differential point-counting method. Results: Particles of both materials were observed partially filling the cervical alveolar third and the volume fraction of inorganic graft was larger than that of organic graft 2 and 9 weeks following implantation. Although evoking neither a foreign-body reaction nor a persisting inflammatory response, both materials delayed bone healing. By the 2nd week, the delay was more pronounced in the animals grafted with inorganic than in those grafted with organic bone, but only in the animals whose inorganic graft occupied more than 50% of the cervical third. By the 9th week, despite the greater volume fraction of inorganic graft the percent of bone healing was similar to that observed in the animals grafted with organic bone. Conclusion: The degree of impairment of bone healing resulted from combination of factors such as type of material, its relative amount and the phase of the reparational process.