Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review.

Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. BACKGROUND: Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. METHODS: Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). RESULTS: Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. CONCLUSION: Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.

Gene expression in human adipose-derived stem cells: comparison of 2D films, 3D electrospun meshes or co-cultured scaffolds with two-way paracrine effects.

Finding the appropriate cues to trigger the desired differentiation is a challenge in tissue engineering when stem cells are involved. In this regard, three-dimensional environments are often compared to cells' two-dimensional culture behaviour (plastic culture dish). Here, we compared the gene expression pattern of human adipose-derived stem cells (ASC) seeded in a three-dimensional (3D) electrospun mesh and on a two-dimensional (2D) film - both of exactly the same material. Additionally, we conducted experiments with a scaffold floating above a film to investigate two-way paracrine effects (co-system). Electrospun meshes (3D scaffolds) and films (2D), consisting either of pristine poly-lactic-co-glycolic acid (PLGA) or of PLGA-containing dispersed amorphous calcium phosphate nanoparticles (PLGA/aCaP), were seeded with ASCs and cultured either in Dulbecco Minimum Essential Medium (DMEM) or in osteogenic medium. After two weeks, minimum stem cell criteria markers as well as typical markers for osteogenesis, endothelial cell differentiation, adipogenesis and chondrogenesis were analysed by quantitative real-time PCR. Interestingly, mostly osteogenic genes of cells seeded on 3D meshes were upregulated compared to those on 2D films, while stem cell markers seemed to be only slightly affected. Runx2 and osteocalcin showed an especially strong upregulation under all conditions, while most other factors analysed for 2D/3D changes were highly dependent on the material composition, the culture medium and on paracrine signalling effects. The beneficial 3D environment for stem cells found in many studies has therefore not to be attributed to the third dimension alone and should carefully be compared to 2D films fabricated of the same material. Furthermore, paracrine interactions triggering differentiation are not negligible.

Buprenorphine for pain relief in mice: repeated injections vs sustained-release depot formulation.

Sustained-release formulations of analgesic drugs are promising alternatives to repeated drug injections. Here, we compared a sustained-release formulation of buprenorphine (SB, 2.2 mg/kg) with a standard protocol of three injections of buprenorphine (Temgesic, 0.1 mg/kg/8 h) in mice. Buprenorphine serum concentration and analgesic action (thermal sensitivity) were determined in healthy mice. Additionally, the pain relief properties of both protocols were assessed after laparotomy using physiological and ethological measures of pain and recovery. Serum concentrations and thermal sensitivity tests indicated duration of action of at least 4 h (but less than 8 h) with the Temgesic protocol, and 24-48 h with SB. Behavioural and clinical parameters indicated at least partial pain relief after surgery for both protocols. Observed side-effects of buprenorphine independent of the protocol were increased activity, disturbed circadian rhythm and several abnormal behaviours. A tendency for decreased food and water intake as well as body weight reduction was also seen. Body weight decreased significantly in animals that received three injections of Temgesic, regardless of whether surgery was performed or not (P = 0.015; P = 0.023), hinting at a stress response towards this repeated intervention. In conclusion, an application interval of 8 h (Temgesic) appears too long and might lead to repeated periods with insufficient analgesia in animals undergoing lasting and/or substantial pain after surgery. In comparison to the standard protocol, SB provided a long-lasting, assured analgesia without possible stressful repeated injections in a standard surgical model, with only limited and acceptable behavioural side-effects.

Echocardiographic evaluation of children with and without family history of essential hypertension.

A family history of hypertension is considered a risk factor for developing hypertension. We studied two groups of normotensive children (aged 14 years): one comprising 14 subjects with family history of hypertension, the other comprising 15 subjects without family history of hypertension. Children were comparable with respect to age, weight, height, body surface area, heart rate, and arterial blood pressure. M-mode echocardiography demonstrated higher interventricular septum/posterior wall ratio in progeny of hypertensive subjects. Interestingly, all the parameters evaluated were within the normal limits. Our data suggest that a certain degree of cardiac changes is present in children with positive family history of hypertension, though further studies are needed before considering these findings predictive of future essential hypertension.

Low incidence of cardiac hypertrophy in essential hypertensives with no retinal changes.

120 subjects, 90 hypertensives and 30 age-matched controls, were evaluated by fundoscopy and echocardiography to assess the degree of target organ involvement. The hypertensive patients were divided into 3 groups (mild, moderate, severe hypertension) according to their diastolic blood pressure levels. No significant difference was demonstrated in left ventricular mass among the 3 groups. Moreover, no relationship was demonstrated between the degree of hypertension and the severity of fundoscopic changes. Our findings indicate that patients with no retinal changes show a low probability of left ventricular hypertrophy and that patients with left ventricular hypertrophy show a high probability of retinal involvement. Our data indicate that fundoscopy is more sensitive than echocardiography in the recognition of the hypertensive disease.

Cranial base hemorrhage. A technique for controlling the uncontrollable.

In the management of trauma, control of life-threatening hemorrhage must be accomplished expeditiously if morbidity is to be decreased and mortality prevented. Hemorrhage from the inaccessible cranial base, especially when transected vessel stumps are not available for direct control, can be the most demanding, life-threatening, surgical emergency. We present our experience in utilizing an autologous bone grafting technique to successfully control severe hemorrhage from the base of the skull. In our review of the literature to date, we have been unable to ascertain whether this modality has been previously used.

Circadian variations of heart rate and premature beats in healthy subjects and in patients with previous myocardial infarction.

Chronobiological analysis of the circadian variations of heart rate, ventricular and atrial ectopies, was carried out on 11 patients with previous myocardial infarction matched with 11 controls. Individual circadian rhythms in heart rate were seen in all the control subjects but only in 6 patients with previous myocardial infarction. The behaviour of the individual circadian rhythms of premature beats was not significantly different between the two groups. A significant group rhythm in ectopies was not demonstrated, nevertheless a trend to higher frequency of arrhythmias during the activity span was detected. These results do not allow to postulate a circadian pattern of arrhythmias common to all the subjects examined. Therefore, the individual circadian behaviour of premature atrial and ventricular beats should be recognized for monitoring antiarrhythmic therapy. A significant group rhythm in heart rate was demonstrated for the two populations studied and linear discriminant analysis showed that the amplitude of this rhythm was significantly lower in patients than in controls. Possibly, myocardial infarction may affect the sinus node function producing a "flattened" range of heart rates during the 24 hours.

Implementation of total quality management after reconfiguration of services on a general hospital unit.

In 1992 the New York State Office of Mental Health issued a statewide plan for mental health services to reduce the number of inpatient beds in state-run facilities from approximately 11,000 to between 6,000 and 8,000 by the year 2000. This reduction resulted in at least a 25 percent increase in psychiatric beds at local general hospitals. In 1992 Albany Medical Center Hospital's department of inpatient psychiatry established an interdisciplinary committee to address changes resulting from the reconfiguration of services to chronic mentally ill persons. The committee established procedures to use the principles of total quality management to respond to problems and to continuously improve the therapeutic milieu. The authors describe how these principles were used to create a patient satisfaction survey, to examine and improve part of the hospital admissions procedure, and to review and revise treatment planning documentation. A concurrent review committee reviews patients' records to ensure accuracy of documentation and quality of care.

Evidence of no interobserver variability in M-mode echocardiography.

Left ventricular internal dimensions, septal and posterior wall thickness, aortic root diameter, and left atrial dimensions, were independently measured by two experienced interpreters on 50 consecutive routinely performed M-mode echocardiograms. The purpose of this work was to evaluate the reproducibility of these measurements and to assess if a different "diagnostic effect" could be provided by the two readers. The extent of interobserver variability was calculated and expressed as a percent of the mean. No significant interobserver variability was found for all the measured echocardiographic parameters and the two interpreters gave rise to the same "diagnostic effects." Therefore, the authors suggest following well stated guidelines to provide uniformity in the process of determining the boundaries of the structures to be measured and adjusting the actual measurements by multiplying by a conversion factor (representing the ratio between the number of 1 cm markers and the distance in centimeters between the first and the last marker), as opposed to interpolating between the marks on the recording paper.

Relationship between systolic time intervals and arterial blood pressure.

It has been suggested that systolic time intervals (STI) can be used to monitor the cardiac effects of antihypertensive treatments and also to evaluate hypertensive patients. STI changes observed in hypertensives have been ascribed to myocardial disease, although they could be due to the existence of a relationship between STI and blood pressure. A group of 37 subjects (18 normotensives and 19 hypertensives) with no signs of heart failure and left ventricular dysfunction were studied to examine the relationship of STI to blood pressure. Pacing with an external battery pulse generator was performed at the rate of 95 beats/min in order to eliminate differences in heart rate. STI were measured from good quality high speed (100 mm/s) recordings and the average value of 10 consecutive cardiac cycles was used for statistical analysis. Normal subjects showed significantly lower values of pre-ejection period (PEP), electromechanical systole (QS2), and pre-ejection period/left ventricular ejection time ratio (PEP/LVET). Moreover, a significant inverse relationship between diastolic pressure and LVET and significant direct relationships between diastolic pressure and PEP, systolic pressure and PEP, diastolic pressure and PEP/LVET, and between systolic pressure and PEP/LVET were demonstrated. We suggest to consider the relation of STI to blood pressure to provide regression equations to best appreciate and use STI.

Does ergometric stress test induce a procoagulative condition in patients with previous myocardial infarction?

A regularly scheduled physical training program seems to have antithrombotic effects. Moreover, the hemostatic changes occurring in patients with coronary artery disease during acute exercise have not been clearly elucidated. Since stress testing is routinely performed in clinical cardiology, it would be helpful to assess whether patients with coronary artery disease are exposed to acute coronary thrombosis during or soon after sustained physical exercise. This study was designed to evaluate the effect of acute physical exercise (stress test by bicycle ergometer) on blood coagulation in a group of patients with previous myocardial infarction, and to determine whether the antithrombotic therapy commonly administered favorably influences hemostatic equilibrium. Our results suggest that exercise testing is not harmful to patients with previous myocardial infarction in regard to hemostasis and fibrinolysis and that antithrombotic therapy reduces postexercise increase in platelets.

Reduction of cardiac toxicity of anthracyclines by L-carnitine: preliminary overview of clinical data.

Doxorubicin is one of the most effective antineoplastic agents but its limited use is due to acute and chronic cardiotoxicity. These side-effects are irreversible and dose-dependent, occurring in one-third of the patients treated after a cumulative dose of 300 mg/m2. It has been suggested that the problem of acute and chronic cardiotoxicity may be prevented by using L-carnitine. Hence nine patients receiving a cumulative dose (200-490 mg/m2) of doxorubicin have been studied. Acute cardiotoxicity has been evaluated by creatine kinase---marsh bender (MB) serum levels before and 15 h after treatment. Data demonstrated no significant increase of isoenzyme-MB after doxorubicin administration. Chronic cardiotoxicity has been monitored studying the electrocardiograph and the left ventricular performance by computerized M-Mode echocardiography measuring the maximal velocity of circumferential fibre shortening (VCF Max) which is considered a reliable and very sensitive non-invasive parameter to evaluate myocardial contractility. The results show a decrease in VCF Max (measured in diameter/cardiac cycle) from 1.7 +/- 0.4 to 1.4 +/- 0.3 but still within normal values. So the systematic use of L-carnitine as adjuvant therapy is proposed during doxorubicin administration.

Echocardiographic assessment of anthracycline cardiotoxicity during different therapeutic regimens.

The use of doxorubicin (Dx) in treating malignancies is limited by a potentially fatal cardiomyopathy. Prevention of this related cardiotoxicity has been attempted either by using doxorubicin analogues such as 4'-epidoxorubicin (4'-EpiDx) or by simultaneous administration of other pharmacological substances. Fifteen patients with breast and lung cancer divided into three groups, treated respectively with Dx alone, Dx and L-carnitine and 4'-EpiDx, were studied to assess the effects of these therapeutic regimens on left ventricular performance. For this purpose the maximum velocities of fibre shortening and lengthening (VcF), obtained by computerized M-Mode echocardiography were used as indices of systolic and diastolic function respectively. Data from patients and from 25 healthy subjects were evaluated by analysis of variance and Tukey test. No significant difference was found in baseline systolic and diastolic VcF values. Significantly lower systolic VcF (p less than 0.05) was shown by patients treated with Dx alone, while diastolic VcF was significantly lower in those treated with 4'-EpiDx after four cycles. Systolic VcF of patients treated with Dx and L-carnitine and with 4'-EpiDx did not significantly differ from controls even after six therapeutic cycles. These data demonstrate that systolic VcF is not affected by 4'-EpiDx or by Dx when administrated with L-carnitine. The reduction of diastolic VcF by 4'-EpiDx and not by Dx could be due to different effects of these drugs on the calcium transport since early isovolumic relaxation depends on an energy-dependent process of calcium removal.

New indices in the evaluation of clonidine transdermal therapy of hypertension.

Since high blood pressure might be more harmful the higher it is and the more it remains above a determined critical value (140/90 mm Hg - 18.7/12.0 k Pa - in the present study), the hyperbaric impact, a measure of the total load exerted on the arterial walls and the total time during the day when blood pressure is elevated above the critical value, have been evaluated. Ten patients with essential hypertension underwent non-invasive automatic 24-h blood pressure monitoring three times (baseline and after three and seven days from the application on the upper chest of a transdermal self-adhesive patch delivering clonidine). The recorder was programmed to measure blood pressure every 30 min during the day and every 60 min during the night. Significantly lower values of blood pressure, hyperbaric impact and duration of elevated blood pressure have been demonstrated from the third day after the beginning of transdermal therapy.

Muscular blood flow in patients with heart failure.

We studied reactive hyperemia in a group of patients with heart failure before and after therapy, since changes in the characteristics of muscular blood flow may influence the functional class of these patients. At the same time we evaluated some echocardiographic parameters too. When the patients improved clinically, they showed an increase in muscular blood flow at rest and in percent of fractional shortening and a decrease in peripheral vascular resistance. The reactive hyperemia did not change significantly. This fact probably depends on a maximal response to the postischemic hyperemia and represents the integrity of autoregulatory mechanisms.

Systolic time intervals during isometric exercise in supine position should be corrected also for arterial pressure.

In this paper we have studied the relationship between the systolic time intervals (STI) and the heart rate (HR) and systolic arterial pressure (SAP) in a group of 24 healthy subjects at three different effort levels during an isometric exercise in supine position and in basal conditions. We observed a decrease of the non corrected STI values during the exercise. Then we corrected STI using the regression equations obtained by plotting STI values versus the corresponding HR values at rest and during the exercise. We showed an increase of corrected left ventricular ejection time (LVET) during the whole exercise, and an increase of corrected total electromechanical systole (QS2c) at 50% effort level and then a return to the basal values. We also derived the multiple regression equations correlating QS2 and LVET with HR and SAP. Notwithstanding these equations show a significant positive correlation between the two STI considered and SAP only at the maximum effort, we corrected LVET and QS2 values by these equations assuming that the relationship between these parameters exists also in basal conditions and during the remaining stages of the exercise. By this correction we found a decrease of LVETc and QS2c in accordance with hemodynamic data reported by other authors. We may conclude that it seems useful to correct the STI obtained during isometric exercise in supine position both for HR and SAP.

STI usefulness during isometric exercise in labile hypertensive patients.

Measurement of the left ventricular systolic time intervals (STI) was considered a valid method in demonstrating the presence of a state of beta-drenergic hyperstimulation. The authors used this method during isometric exercise to differentiate between a group of 16 normal subjects (N) and 16 random labile hypertensives (LH), and between the N and 16 fixed hypertensives (FH). Exercise resulted in a general shortening (p less than 0.01) of the STI, an increase (p less than 0.01) in the systolic arterial pressure (SAP), and an increase (p less than 0.01) in the heart rate (HR) in all the groups studied. The study also demonstrated that the state of blood pressure (diagnosis) alone does not significantly influence the course of the exercise test, and that the interaction diagnosis-exercise gives quantitatively different results in the three groups, to the extent that it is possible to recognize a specific polygraphic pattern for the LH. In this group there is a greater shortening of the Q--S2 and the non-corrected LVET (p less than 0.01) than for the N. The behaviour for the FH falls between the other groups, but it is not possible to distinguish clearly between this group and its neighbour on either side. We conclude that the measurement of the STI during isometric exercise could be useful in determining a diagnostic pattern for subjects who show a lability in their blood pressure.

Computerized M-mode echocardiography in the assessment of cardiovascular effects during intravenous administration of amiodarone.

Antianginal and antiarrhythmic long term therapy with amiodarone may be associated with side effects, therefore it should be used mainly in short term treatment of severe arrhythmias and acute coronary insufficiency. It is important to assess if any inotropic effect may be produced after intravenous administration of this drug in commonly accepted therapeutic doses (5 mg/kg body weight). To investigate this possibility we studied the effects of amiodarone on blood pressure (BP), on heart rate (HR) and on the maximal velocity of circumferential fiber shortening (Vcf Max). Simultaneous echocardiogram (UCG), electrocardiogram (lead DII) (ECG) and BP cuff measurement were performed on 12 subjects without cardiomegaly and clinical evidence of heart failure, immediately before a 30 second intravenous injection of amiodarone and every 30 seconds over a period of 6 minutes after drug administration. Amiodarone administration markedly raised HR within the first 30 seconds from the beginning of the injection and concomitantly decreased diastolic BP. No significant lowering of systolic BP was observed. Vcf Max (circ/sec) raised during the test concomitantly with HR increase, showing a significant relationship between left ventricular performance and HR. The same was also true during atrial pacing performed on one subject. No significant changes in any of the parameters studied were demonstrated after placebo (saline solution) administration to two presumable healthy subjects. Amiodarone does not seem to have any positive or negative intrinsic inotropic effect when administered intravenously at a dose of 5 mg/kg body weight.

Effects of isoproterenol and methoxamine on the electrocardiogram.

The effects of isoproterenal (ISP) and methoxamine (MTX) infusion in 20 asymptomatic subjects with labile T wave were studied. In those treated with ISP the T wave showed an early negative trend and later became clearly positive in 5 subjects. In the majority of the subjects treated with MTX the T wave became positive. T wave changes match variations of both the ventricular gradient and, to a lesser degree, the QRS area. These changes were not related to heart rate or, in the subjects treated with MTX, to the baroreceptorial sensitivity deduced from the slope of the regression equation between R-R internal and systolic arterial pressure. The results of this study confirm the existence of a neurogenic mechanism affecting the electrocardiographic changes in T wave.

Bioavailability of digoxin and beta-methyl-digoxin.

In a randomized crossover study the bioavailability of a single dose of digoxin and of beta-methyl-digoxin tablets was tested in four normal volunteers. No difference was found between the two products in the rate and extent of drug absorption using 6 day cumulative urinary excretion and serial serum concentration measurements.