Experimental evidence of pharmacological management of anchorage in Orthodontics: A systematic review.

INTRODUCTION: Orthodontic anchorage is one of the most challenging aspects of Orthodontics. Preventing undesired movement of teeth could result in safer and less complicated orthodontic treatment. Recently, several reviews have been published about the effects of different molecules on bone physiology and the clinical side effects in Orthodontics. However, the effects of local application of these substances on the rate of orthodontic tooth movement have not been assessed. OBJECTIVES: The aim of this research was to analyze the scientific evidence published in the literature about the effects of different molecules on orthodontic anchorage. METHODS: The literature was systematically reviewed using PubMed/Medline, Scopus and Cochrane databases from 2000 up to July 31st, 2014. Articles were independently selected by two different researchers based on previously established inclusion and exclusion criteria, with a concordance Kappa index of 0.86. The methodological quality of the reviewed papers was performed. RESULTS: Search strategy identified 270 articles. Twenty-five of them were selected after application of inclusion/exclusion criteria, and only 11 qualified for final analysis. Molecules involved in orthodontic anchorage were divided into three main groups: osteoprotegerin (OPG), bisphosphonates (BPs) and other molecules (OMs). CONCLUSIONS: Different drugs are able to alter the bone remodeling cycle, influencing osteoclast function and, therefore, tooth movement. Thus, they could be used in order to provide maximal anchorage while preventing undesired movements. OPG was found the most effective molecule in blocking the action of osteoclasts, thereby reducing undesired movements.

Clodronate prevents osteopenia and loss of trabecular connectivity in estrogen-deficient rats.

Daily oral clodronate treatment was evaluated in Sprague-Dawley rats for its ability to inhibit estrogen-deficiency-induced changes in femoral neck, femoral diaphysis, and lumbar vertebrae (L4-L5). Six-month-old ovariectomized (OVX) rats were administered by gavage a vehicle (Veh) or clodronate (100 or 500 mg/kg/day). Sham-operated (SHAM) control rats received the vehicle (n = 15/group). Treatment was started on the day of operation and continued for 3 months. Trabecular bone volume (BV/TV) and structural variables (trabecular number, Tb.N; thickness, Tb.Th; separation, Tb.Sp; and trabecular bone pattern factor, Tb.Pf) were assessed on secondary spongiosa of the right femoral neck Furthermore, cantilever bending test of the left femoral neck and compression test of L4, ash weight of L5, and morphometric studies of femoral diaphysis were carried out, and serum and urinary markers of bone turnover were determined. The OVX/Veh group had higher levels of serum osteocalcin and alkaline phosphatase and higher urinary excretion of deoxypyridinoline/creatinine than the SHAM/Veh group at 3 months postsurgery, and clodronate reduced these changes. BV/TV of femoral neck, bone mass of L5, and the maximum loads of the femoral neck and L4 were lower after OVX than SHAM operation. Although clodronate prevented trabecular bone loss in the femoral neck and preserved Tb.Pf at the SHAM control level, it failed to preserve the mechanical strength at the femoral neck However, in lumbar vertebrae, clodronate prevented the loss of bone mass and mechanical properties. Furthermore, there was a good positive correlation between maximum load of L4 and the ash weight of L5 (n = 58, r = 0.69, p < 0.001). In the femoral neck (n = 55), Tb.Pf correlated negatively with BV/TV and Tb.N (r = -0.59 and r = -0.55;p < 0.001, respectively) and positively with Tb.Sp (r = 0.61, p < 0.001). In femoral mid-diaphysis, there were no significant changes in cortical bone geometry in any of the groups. We conclude that orally administered clodronate suppresses the enhanced bone turnover in adult OVX rats and preserves trabecular bone volume and connectivity in the femoral neck In the axial skeleton, clodronate has a beneficial effect on lumbar vertebral bone mass and strength.

Treatment of hypercalcaemia of malignancy with clodronate.

The bisphosphonate clodronate has been widely used in the treatment of hypercalcaemia and osteolytic bone metastases. It can normalize plasma calcium in most hypercalcaemic, rehydrated cancer patients when increased bone resorption is the prevailing disturbance of calcium metabolism. When given intravenously either as a single infusion or as repeated daily administrations, serum calcium levels fall to normal 3-5 days after the onset of therapy. Long-term maintenance treatment must be adjusted individually since relapse appears to depend upon the tumour type, the degree of malignancy and any anticancer therapy. In patients in whom increased tubular calcium reabsorption is the prevailing disturbance of calcium metabolism, the effect of clodronate on plasma calcium is incomplete, despite the normalization of bone resorption. This type of therapeutic response can be reproduced experimentally in bisphosphonate-treated animals receiving a constant infusion of parathyroid hormone-related peptide, a peptide isolated from various tumour types including lung, kidney, breast and neuroendocrine tumour of the pancreas. In patients having a good response to clodronate, the fall in plasma calcium is accompanied by an increase in the calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3. This homeostatic response probably explains why hypocalcaemia occurs rarely in clodronate-treated patients. No serious side-effects of treatment have been reported. Clodronate appears to be a safe and effective treatment for the hypercalcaemia of malignancy, where increased bone resorption is the major mechanism disturbing the homeostasis of extracellular calcium.

Clinical utility of clodronate in the prevention and management of osteoporosis in patients intolerant of oral bisphosphonates.

Bisphosphonates have a long history in the treatment of osteoporosis and bone-related disease. This review focuses on the use of a specific nonaminobisphosphonate, clodronate, which appears to be much better tolerated than other bisphosphonates and free of high-risk contraindications. Specifically, this paper reviews its use in the prevention of osteoporosis in postmenopausal women, taking into account its tolerability profile and recent safety issues arising regarding the use of bisphosphonates.

Bacterial adhesion to bisphosphonate coated hydroxyapatite.

Staphylococcus aureus (S. aureus) is commonly associated with microbial infection of orthopaedic implants. Such infections often lead to osteomyelitis, which may result in failure of the implant due to localised bone destruction. Bacterial adhesion and subsequent colonisation of the device may occur as a consequence of contamination during surgery, or by seeding from a distant site through the blood circulation. Coating of the hydroxyapatite (HA) ceramic component of artificial hip joints with the bisphosphonates clodronate (C) and pamidronate (P) has been proposed as a means to minimise osteolysis and thereby prevent loosening of the implant. However, the effect of the bisphosphonate coating on bacterial adhesion to the HA materials must be determined before this approach can be implemented. In this study coated HA materials were incubated with the S. aureus and the number of adherent bacteria determined using the Modified Vortex Device (MVD) method. The number of bacteria adherent to the P coated HA material was significantly greater than that adherent to uncoated HA (60-fold increase) or to the C coated HA (90-fold increase). Therefore, even though earlier studies suggested that P bound to HA may improve osseointegration, the results presented would suggest that the use of this coating may be limited by the potential increased susceptibility of the coated device to infection.

Short-term intermittent intravenous clodronate in the prevention of bone loss related to chemotherapy-induced ovarian failure.

Chemotherapy-induced ovarian failure causes rapid bone loss in premenopausal women with early breast cancer. The aim of the present study was to investigate the effect of intravenous intermittent clodronate during adjuvant chemotherapy in prevention of this rapid bone loss. 45 premenopausal women with early stage breast cancer were treated with adjuvant chemotherapy. In addition, all women were randomly allocated to receive either seven cycles of intravenous clodronate infusions (1500 mg each) parallel to the chemotherapy or no further therapy. The mean bone loss in the lumbar spine at 6 months was -0.5% in the clodronate group and -1.4% in the control group (p = 0.22) and, at 12 months, -3.9% and -3.6%, respectively (p = 0.62). Type I collagen metabolite PINP levels at six months were significantly lower in the clodronate group than in the control group: 22.6 microg/l (range 15.7-55.8 microg/l) and 44.0 microg/l (range 12.5-91.9 microg/l), respectively (p = 0.0001). At 12 months, no difference between the PINP levels in clodronate and control groups were seen. In conclusion, in this small study a short-term intermittent intravenous clodronate treatment did not seem to prevent clinically significantly the bone loss related to chemotherapy-induced ovarian failure in premenopausal women with early stage breast cancer, even though a significant reduction of a biochemical marker of bone turnover (PINP) was seen during the therapy.