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Delayed Fracture Healing in Diabetics
with Distal Radius Fractures
Opožděné hojení zlomenin u diabetiků se zlomeninou distálního radia
S. PSCHERER1, G. H. SANDMANN2, S. EHNERT3, A. K. NUSSLER3, U. STÖCKLE3, T. FREUDE3
1 Abteilung für Innere Medizin-Diabetologie, Klinikum Traunstein, Traunstein, Germany2 Klinik und Poliklinik für Unfallchirurgie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany3 Berufsgenossenschaftliche Unfallklinik Tübingen, Eberhard Karls Universität Tübingen, Tübingen, Germany PURPOSE OF THE STUDY Diabetics may have an increased fracture risk, depending on disease duration, quality of metabolic adjustment and extent of comorbidities, and on an increased tendency to fall. The aim of this retrospective one-centre study consisted in detectingdifferences in fracture healing between patients with and without diabetes mellitus. Data of patients with the most commonfracture among older patients were analyzed.
MATERIAL AND METHODS Classification of distal radius fractures was established according to the AO classification. Inital assessment and follow-up were made by conventional X-rays with radiological default settings. To evaluate fracture healing, formation of callus andsclerotic border, assessment of the fracture gap, and evidence of consolidation signs were used.
The authors demonstrated that fracture morphology does not influence fracture healing regarding time span, neither concerning consolidation signs nor in fracture gap behaviour. However, tendency for bone remodeling is around 70% lowerin investigated diabetics than in non-diabetics, while probability for a successful fracture consolidation is 60% lower.
To corroborate the authors hypothesis of delayed fracture healing in patients with diabetes mellitus, prospective studies incorporating influencing factors like duration of metabolic disease, quality of diabetes control, medical diabetes treatment,comorbidities and secondary diseases, like chronic nephropathy and osteoporosis, have to be carried out.
Key words: diabetes, delayed fracture healing, distal radius fractures, callus formation, blood glucose level, osteoblasts.
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MATERIAL AND METHODS
Diabetes is one of the frequent metabolic diseases in In this study, patients that have been treated with a uni- the industrialized countries. Up to 2030, 366 million lateral or bilateral distal radius fracture that were treated people will be suffering from diabetes. This corresponds with a volar locking plate osteosynthesis (Aptus Radius to a doubling of the prevalence in 30 years (34). Also 2.5/Medartis GmbH) at the Dept. of Traumatology of among adolescents, an increasing prevalence of type 2 the Klinikum rechts der Isar of the Technische Universität diabetes has been demonstrated, which is due to poor München between January 2007 and February 2010 have nutrition, juvenile obesity, and the decreasing physical been included. The patient data were recorded retro- activity of the youth aged under 18 years (8). Therefore, spectively. A vote of the ethics committee was not re- diabetes is becoming one of the big players in health On the other hands, patients with a prolonged post- The chronic-progredient disease can cause macro- operative immobilisation of the wrist (≥ 4 weeks) or and microvascular changes as well as nerve damage with a postoperative wound healing disorder have been and wound healing disorders with serious consequences, excluded from this study. Other exclusion criteria were which entail very cost-intensive treatment regimes. Be- the use of steroids, of phenprocumoron, and of immuno- sides the frequent "classic" secondary diseases, diabetic suppressive medication, the existence of a malignant un- osteopathy is the most underrated side effect of long- derlying disease, the proof of a hepatic impairment (sero- time diabetes mellitus. Depending on the time that has logical), identified bony non-unions, and insufficient passed since the onset of diabetes, the quality of regu- compliance of the patient.
lation of the metabolism and the extent of secondary The radiological assessment was performed after the diseases, like e.g. peripheral sensomotoric polyneuropa- inital trauma, intraoperatively via fluroscopy, on the day thy and diabetic retinopathy, diabetics may dispose of after surgery and at the 6-week post-treatment normal an increased tendency to fall, and therefore of an in- follow-up in this clinial set-up. Postoperatively, the creased incidence of fractures. Despite these external forarm was immobilized over 4 weeks with a dorsal 1/3 risk factors, the number of long bone fractures is splint, day and night. After the second week, the splint strongly elevated in type 1 as well as in type 2 diabetics.
was removed for the passiv-assistive physiotherapy train- This increase is caused by diabetic osteopathy (2, 25, ing of the wrist three times a week.
During the registration of the patient data from the While the bone mineral density is reduced by hyper- patient s records, the patient s age, the relevant comor- calciuria and a defective bone formation among other bidities, the current medication as well as the body mass things in type 1 diabetics, the situation is much more index (BMI) which was calculated from the weight and complex in type 2 diabetics. Despite a normal or elevated the height (Table 1), were documented. All patients have bone mineral density compared to the age-related healthy been informed and only enroled in the study after having population, the type 2 diabetics dispose of an insufficient signed an informed consent form.
bone quality (1, 15) and the risk of fractures is consider- Fracture classification. The classification of the distal
ably increased in this group of patients (17). More recent radius fractures was carried out by using the x-rays data have revealed a decreasing bone density in type 2 which had been performed preoperatively according to diabetics depending on the extent of the insulin resistance the AO classification based on the radiographs taken in and on an existing hyperinsulinemia (28).
2 planes in accordance with the radiological default set- As type 2 diabetes often correlates with long-lasting tings (Table 2). This classification was reviewed once obesity, it is believed that the increased bodyweight again by two indepenent traumatologists at the retro- causes a mechanical stimulation of the bone, which spective evaluation of the radiographies. might explain the elevated bone mineral density (7). Itis assumed that the reduced bone quality is due to animbalance between the organic and inorganic matrixsurrounding the osteogenetic cell pool (10).
In the future, it is indispensable to gain a better un- derstanding of the pathophysiology in diabetic bone dis- Number of patients (%) ease. Due to the disorders in blood circulation and wound healing, fracture healing is further complicated. The bad convalescence leads to a reduced quality of life and Mean age ± SD (range) 73.1 ± 12.8 (50.7–89.2) 56.7 ± 18.6 (15.4–95) eventually to an important loss of independence of the 24.5 ± 3.8 (17.7–30) 24.5 ± 3.9 (17.6–47.5) patients. The goal of the present retrospective study con-sisted in answering the question, if the differences con- 73.9 ± 22.1 (26.4–104.1) 82.5 ± 21.6 (20.5–104.1) cerning the fracture consolidation can be found between Chronic renal insufficiency diabetic and non-diabetic patients in the distal radius fracture, the most common traumatic fracture type in older patients.
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In terms of a beginning bone remodeling at the fracture site, the bone remodeling tendency of diabetics was Type of fracture around 70% lower than that of non-diabetics (odds ratio: (AO classification) N (% of the respective group) 0.310; 95% CI: 0.11-0.89; p = 0.029). After age stan- dardization, no usable significance was found. No cor- relation was found between the closing of the fracture gap and the time between admission and operation. The mean time span was 1.7 days.
4. Fracture consolidation. At the follow-up exami-
nation after 6 weeks, 7 patients (41.2%) out of the group of diabetics exhibited no signs of consolidation in thegroup of diabetics, while in the control group, 39 patients Fracture healing. For the assessment of fracture heal-
(22.3%) demonstrated no such signs. On the other hand, ing, three criteria were used. The conventional postop- 9 patients (52,9%) among the diabetics and 130 patients erative images (1-2 days postoperative) were compared (74.3%) from the control group, demonstrated clear signs by two surgeons and one radiologist with the control ra- of consolidation. However, only one patient (5.9%) out diographies which were taken with an identical radi- of the diabetics group and 6 patients (3.4%) out of the ographic technique after 6 weeks (+/- 1 week).
control group exhibited a complete consolidation – Criterion 1: Formation of callus or of a sclerotic border (p = 0,118).
– Criterion 2: Evaluation of the fracture gap (stage 1: According to these results, the probability of a suc- fracture gap unchanged from the control, stage 2: frac- cessful fracture consolidation of diabetics is 60% lower ture gap no longer detectable) than that of non-diabetics (odds ratio: 0.410; 95% CI: – Criterion 3: Proof of signs of consolidation (stage 1: 0.15-1.15; p = 0.089). If the age of the patients has been no signs of consolidation, stage 2: proof of beginning adjusted, the prognosis for a successful fracture consol- consolidation, stage 3: consolidation) idation tends to be lower in diabetics, but these numbersindicate only a tendency. However, no dependence was found between the consolidation and the time elapsedfrom the accident to the surgery.
1. Fracture morphology. The defined signs of frac-
In the aforementioned period, 192 patients with distal ture healing (see above) were not influenced by the frac- radius fractures were included in the study. Their mean ture morphology over the first 6weeks after open reduction and in-ternal fixation, neither concerning thesigns of consolidation, nor concern-ing the evaluation of the behavior ofthe fracture gap.
2. Callus formation. Out of the
192 patients, which received a fol-low-up examination, 149 patients exhibited a radiologically verifiablecallus formation after 6 weeks. How-ever, 43 patients demonstrated no cal-lus formation at all. Among the dia-betic patients (n = 17), 10 patientsexhibited callus formation, while nocallus formation was visible in 7 pa-tients.
In comparison to non-diabetic pa- tients, a Fisher's exact test showedno significance (p = 0.067) whichsuggests a delayed callus formationin diabetics.
3. Fracture gap. Stage 1 (un-
changed to the control): 9 patients(52.9% of the diabetics) aginst 51non-diabetic patients (29.1%). Stage2 (fracture gap no longer detectable):1 patient (5.9% of the diabetics) Fig. 1. Fracture gap 4 weeks postoperative. Black: Fracture gap unchanged in com- against 6 non-diabetic patients parison to the post-operative control. White: Fracture gap no longer detectable. Odds ratio: 0.310; CI: 95% (0.11–0.89); p = 0.029 268_273_pscherer 7.8.15 8:56 Stránka 271 271/ ACTA CHIR. ORTHOP. TRAUM. ČECH., 82, 2015
age was 73.1 years (50.7-89.2). Out of the 192 patients This increased fracture risk in diabetics (30) and the who participated at the follow-up examination, 149 pa- associated fracture healing and wound healing are due tients in total exhibited a radiologically detectable callus to multiple factors which have been intensively investi- formation after 6 weeks, while in the remaining 43 pa- gated. However, it depends on the duration of diabetes tients, no callus formation was visible. In the group of and on the comorbidities, like e.g. retinopathy, and on the diabetic patients (n = 17), 10 patients exhibited a cal- the diabetic neuropathy (18, 21).
lus formation, in 7 patients, no callus formation was vis- Contrary to the reduced bone mineral density of pa- ible. A Fisher s exact test showed no significant differ- tients with type 1 diabetes, type 2 diabetics exhibit nor- ence between diabetic and non-diabetic patients, mal to elevated values of bone mineral density (BMD), (p = 0,067), which would suggest a delayed callus for- (29). In a study with a duration of twelve years, no loss mation in diabetics.
of bone mineral density was detected in type 2 diabetics The fracture morphology had no influence on fracture in comparison to the range of the normal population healing. In the framework of the 6 weeks follow-up, ra- (14). In a prospective cohort study with a mean follow- diographs demonstrated no change of the fracture gap up of 9.8 years, intra-articular fractures occurred more in 9 diabetic patients (52.9%) as well as in 51 non-dia- than twice as frequently in women with diabetes mellitus betic patients (29.1%). On the other hand, after six as in non-diabetic women (32).
weeks, the radiographs did no longer indicate any frac- The bone mineralization is regulated by the parathor- ture gap in one diabetic (5.9%) and in 6 non-diabetic mon, the growth hormone, by calcitriol, the bone mor- patients (3.4%).
phogenetic protein (BMP), and the vitamin D3 protein, Regarding the beginning bone remodeling, the ten- as well as by IGF (insulin-like growth factor), TGF-ß dency for bone remodeling was around 70% lower in (tumor growth factor-beta), and other cytokines (14).
diabetics than in non-diabetics (odds ratio: 0.310; 95% The influence of the systemic factors circulating in the CI: 0.11-0.89; p = 0.029). After having performed the blood, like e.g. TGF-ß, and of the blood glucose reducing age standardization, no significance was detected. Re- medication on the bone mineralization is of peculiar in- garding the changes of the fracture gap, no direct corre- terest (27). The influence of elevated TGF-ß levels on lation to the timepoint of the surgery was found. At the human osteoblasts has already been proven in vitro. It 6 weeks follow-up, 7 (41.2%) diabetic and 39 (22.3%) has been demonstrated that glucose and the additional non-diabetic patients exhibited no signs of consolidation.
administration of insulin lead to a stimulation of TGF- On the other hand, 9 (52.9%) diabetic patients and 130 ß, which does not depend on its concentration. Due to (74.3%) patients belonging to the control group demon- the elevated levels of TGF-ß, an increased proliferation strated clear signs of consolidation.
of the osteoblasts as well as a decrease of the AP activity Finally, in 1 (5.9%) diabetic patient and in 6 (3.4%) and a reduced matrix formation occur, which probably non-diabetic patients out of the control group, the con- have a negative effect on bone formation (6).
solidation had already been completed by the time of Further research has demonstrated a correlation be- the six-week follow-up (p = 0.118). The chance of a suc- tween insulin and glucose levels on the one hand and cessful fracture consolidation is 60% lower in diabetics the expression of osteocalcin, a key protein of the bone- than in non-diabetics (odds ratio: 0.410; 95% CI: 0.15– forming cells (osteoblasts) on the other hand (9, 13, 31).
1.15; p = 0.089). If an age adjustment is carried out The time of the initial diagnosis of the diabetes mel- however, the prognosis for a succcessful fracture con- litus, and consequently the duration of the chronic meta- solidation tends to be lower for diabetics than for non- bolic disease, is not known for all patients. Moreover, diabetics, but this is only a tendency. Nevertheless, no the quality of the blood glucose control cannot be traced correlation was found between the consolidation and in the patient sample neither throughout the years, nor the time span between the accident and the surgery.
during the treatment period of the radius fracture.
In type 2 diabetics, a lower bone turnover is charac- terized by reduced bone markers, like e.g. osteocalcin,and C-terminal telopeptide (12). The hyperglycemia also In the retrospective single-center study at hand, a ten- contributes to the formation of high concentrations of dency for delayed fracture healing in patients suffering advanced glycation end-products (AGE) in the collagen, from diabetes type 2 and a radius fracture in comparison which, in turn, leads to changes in the bone density (26).
to the non-diabetic control group was found. Interest- AGEs accumuliate with increasing age, but are also con- ingly, the fracture morphology does not offer any radio- siderably elevated in patients suffering from diabetes, logically recognizable influence on fracture healing. Fur- and contribute to the diabetes-related complications (3, thermore, no differences were found neither in the signs 4). In the analysis of the cell lines. The authors have of consolidation, nor in the changes of the fracture gap been able to show that osteoblastic cells, isolated out of according to the fracture types of the AO classification.
fetal rat ovaria, cultured on AGE-modified type I colla- However, the diabetic patients exhibited a delayed callus gen, these AGEs could be inhibited dose-dependently formation and their tendency for bone remodeling was (11). Furthermore, advanced glycation end-products have reduced by 70% in comparison to the non-diabetic pa- lead to an increase of the bone resorption which has been induced by osteoclasts (22).
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The authors suppose that the quality of the blood glu- dition to a therapy with calcium, vitamin D, and bispho- cose control and the physiological blood glucose have sphonate therapy has had positive effects on total body a considerable effect on fracture healing. On this premise, BMD and total hip BMD among elderly hip fracture pa- a routine determination of the HbA1c level has to be stipulated. In this way, an early optimization of the bloodglucose level can be carried out immediately after the surgery, if the individual HbA1c target value has notbeen reached. Thereby it might be an advantage to opti- Due to the delayed fracture healing, an intensified mize the blood glucose level pre- and perioperatively and multidisciplinary treatment is necessary in order to by changing the oral antidiabetic treatment into insulin ensure a treatment with as little complications as possi- ble. This concerns the soft tissue management as well For the treatment of type 2 diabetes, there already ex- as the fracture treatment and the follow-up, together ists a multitude of oral antidiabetics with different modes with an optimized regulation of the blood glucose level.
of action. Furthermore, the skeletal effects of the treat- This could cause a change in the assessment and the ment of diabetes have only been fragmentarily investi- treatment of fractures in diabetics, as the fracture no gated so far. At this time, there exist no prospective stud- longer has to be regarded as such, but only as the symp- ies analyzing if the patients benefit from the treatment tom of an existing systemic disease, which still has to with oral antidiabetics (OAD) as a monotherapy, as be treated with an osteosynthesis, whereas the success a combination of different OADs or in conjunction with of the therapy depends on the complex treatment of the insulin, as a basally supported oral therapy (BOT) or as underlying disease.
an exclusive insulin therapy (CT, ICT) with regard to In order to corroborate the authors thesis of the de- layed fracture healing in patients suffering from diabetes, Glitazones have a negative influence on bone quality, prospective studies, which take into consideration the as they cause an "unbalanced bone remodelling" which factors mentioned above, are currently carried out.
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Dr. Stefan Pscherer
Abteilung für Innere Medizin-Diabetologie
83278 Traunstein, Germany
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The quest to cost effectively meet recycled water standards with preozonation and biologically active filtration
THE QUEST TO COST EFFECTIVELY MEET RECYCLED WATER STANDARDS WITH PREOZONATION AND BIOLOGICALLY ACTIVE FILTRATION Kurt Ohlinger*1, Carla De Las Casas2, William Yu1, Steve Ramberg1, Rion Merlo2, and Denny Parker2 1 Sacramento Regional County Sanitation District, 10060 Goethe Rd. Sacramento, CA 95827 2 Brown and Caldwell, 201 N. Civic Dr., Suite 115, Walnut Creek, CA 94596 *[email protected] ABSTRACT The latest NPDES permit adopted for the Sacramento Regional Wastewater Treatment Plant included a requirement for tertiary treatment, equivalent to the water quality requirements of Title 22, unrestricted use recycled water. Initial cost projections for the required plant upgrades exceeded $2 billion to upgrade the 691 ML/day (181 mgd) facility. To help in the selection process for tertiary treatment alternatives, a demonstration scale study was undertaken. A 0.95 ML/Day (0.25 mgd) BNR process was constructed to feed three filtration and three disinfection processes operated in parallel. Filtration alternatives tested were granular media, conventional and biologically active, and membrane. Disinfection alternatives were chlorine, ozone, and UV. Objectives of the demonstration scale study were determination of performance of and life cycle costs for each process alternative. The performance and costs for each process alternative will be reported in the presentation, along with trace organic compound removal performance for 12 tested compounds. KEYWORDS Filtration, Disinfection, Title 22, Trace Organic Compounds, Tertiary Treatment, Cost, Ozone, UV, Chlorine, Membrane INTRODUCTION The Sacramento Regional County Sanitation District (District) owns and operates the Sacramento Regional Wastewater Treatment Plant (SRWTP), a high purity oxygen activated sludge (HPOAS) system with chlorine disinfection and sulfur dioxide dechlorination, with permitted discharge to the Sacramento River. Recent discharge permit revisions specify stricter discharge requirements than the existing HPOAS process is capable of meeting. New permit requirements include ammonia and nitrate limits and tertiary treatment to produce the equivalent of California Title 22, unlimited use reclaimed water quality effluent. To identify the most cost-effective treatment technologies to implement, the District embarked on the Advanced Treatment Technology Pilot (ATTP) Project to demonstrate that the new treatment technologies selected by the District will meet the new permit requirements, possible future permit limits, and to refine criteria for detailed design. Through a series of technology selection workshops that culminated in the plan to conduct the ATTP project, the District selected three filtration alternatives and three disinfection alternatives to test. Filtration alternatives consisted of membrane filtration (MF), conventional granular media filtration (CGMF), and biologically active granular media filtration preceded by ozonation
Iranian Journal of Mathematical Chemistry, Vol. 4, No. 1, March 2013, pp. 91 − 109 QSAR Modeling of Antimicrobial Activity with Some Novel 1,2,4- Triazole Derivatives, Comparison with Experimental Study AHRA ROSTAMI , ABBAS AMINI MANESH AND LEILA SAMIE Department of Chemistry, Payame Noor University, I. R. of Iran