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. 2020 Aug 15;14:94–100. doi: 10.1016/j.jcot.2020.08.004

Assessment of union in fractures: Role of Serum Alkaline Phosphatase and Ultrasonography

Himanshu S Rathwa 1, Tarun Verma 1, Viswanath H Chavali 1,∗
PMCID: PMC7920160  PMID: 33717902

Abstract

Introduction

Fracture union is a fundamental goal in orthopaedics. There is variability in assessment and lack of consensus on reliability of various methods to evaluate progress of union. The purpose of this study was to study the temporal association of non-conventional methods i.e. Serum Alkaline Phosphatase (ALP) and Ultrasound (USG) in assessment of fracture healing with reference to plain radiographs (X-ray).

Methodology

This was a prospective observational cohort study of 161 adult patients with surgically treated long bone diaphyseal fractures. Plain radiographs, ALP and USG evaluation was done every 6 weekly for 6 months. USG evaluation included assessment of echogenicity and Doppler measurement of Vascular Resistance Index (RI) of callus. Fractures were considered united when X-ray showed bridging callus. ALP and USG changes over the follow-up period were analysed based on the final outcome of fractures.

Results and conclusion

151 patients showed signs of fracture union at final follow-up. ALP which peaked at 6 weeks in all cases always remained within the laboratory reference range in cases progressing to union; whereas in cases of non-union the levels recorded higher. ALP value was the earliest positive predictor showing progress towards union. Beyond 12 weeks, Hyperechogenicity on Gray scale USG and serial measurement of RI on Doppler USG were found to better confirm progress in fracture union than X-rays. Combined evaluations of ALP and USG appear as promising investigations in assessment of the progress in fracture union.

Keywords: Fracture healing, Non-union, Ultrasonography, Vascular resistive index, Alkaline phosphatase

1. Introduction

Fracture union is not a one step event, but a continuum of overlapping stages. It is a process which starts right at the time of injury and progresses for an unpredictable period of time. A considerable disagreement exists in the clinical and radiographic criteria to define fracture union as well as the average time required for diagnosis of delayed union or non-union.1 Although clinical appreciation combined with plain radiographic assessment2, 3, 4, 5, 6 is routine, other methods to monitor and document bone healing like CT, MRI, Bone scintigraphy etc have been used sparingly in select cases. However in addition to the concern of availability, these advanced investigations pose an added financial burden and/or radiation risk. Better understanding of non-conventional investigations which assess union, may improve our approach towards fracture treatment and possible time for intervention in cases of doubtful progressive union. The aim of this study was to study the temporal association of non-conventional methods i.e. Serum Alkaline Phosphatase (ALP) and Ultrasound (USG) in assessment of fracture healing with reference to Plain radiographs (X-ray) so as to ascertain their applicability in a regular clinical setting.

2. Methodology

This prospective observational study was carried out in the department of Orthopaedics, at a state-run tertiary care hospital attached to a Post-Graduate teaching institute from June 2018 to October 2019 with due permission from the Institutional Ethics Committee. 170 adult (>18years) patients with Closed or Open Grade-I (Gustilo-Anderson’s) diaphyseal fractures of major long bones i.e. femur, tibia (with or without fibula), humerus and radius-ulna (individual or combined) treated with internal fixation were recruited to the study. Only those patients with normal liver functions confirmed by USG and serum biochemistry were included. Fixation of fractures remained independent of the study which included interlock/enders/rush nailing as well as plating. All patients were followed up for six months at six weekly intervals. At each follow-up all patients were assessed clinically and by plain radiographs for signs of union. In addition to ALP measurement, evaluation of fracture callus by USG for echogenicity and vascular Resistive Index (RI) were performed at each follow-up. ALP was done spectrophotometrically using PNPP kinetic IFCC method with a laboratory reference range of 28–111 IU/L. USG was performed using a Philips iU22 camera equipped with a linear probe with 12-5-MHz resolution, MSK Superficial program and 3D Power Color Doppler. Whereas the authors evaluated fracture healing using X-rays, USG examination of the fracture was done by a radiologist independent of the study without the knowledge of X-ray or other study parameters. We considered a fracture united only when X-rays showed bridging callus, across the fracture in both orthogonal views. A brief overview of the methodology is depicted as a flowchart in Fig. 1.

Fig. 1.

Fig. 1

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Flow chart showing methodology.

3. Observations and results

In this study, 170 patients were enrolled (103 M, 67F) which included 58 cases of upper limb and 112 cases involving the lower limb. Average age of the patients was 36.9 [18,68]years. With 9 patients being lost to follow-up we had 161 patients for final analysis. Our study did not dictate the intervention which was individualised by the treating orthopaedic surgeon. Fractures of the humerus and radius-ulna were preferred to be treated by Dynamic Compression plating (DCP) while fractures of femur were treated by interlock nailing. Reduction in intra-medullary nailed fractures was accepted within the limits defined for such fixations. Average Injury-Surgery Interval was 2.68 days. Fig. 2 shows the observations of the cases as well as an overview of outcome in the study.

Fig. 2.

Fig. 2

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Observations of cases and gross outcome.

3.1. X-ray

We considered a fracture united when X-rays showed bridging bone across the fracture in both orthogonal views. Average union time as assessed on X-rays was 18.11 [6,24]weeks. 151 patients showed signs of union and 10 patients showed non-union by final follow-up. Bridging callus was seen as early as six weeks in 11 patients. Sixty percent of the patients showed signs of union by 18 weeks (Table 1). Simple fractures of humerus, radius-ulna and femur united earlier than other long bones. Comminuted fractures of femur and tibia took maximum time to union. Upper limb fractures healed earlier as compared to lower limb fractures. Comminuted fractures, fracture of upper third shaft and those reduced with gap showed higher chances of ending in non union.

Table-1.

Gross analysis of the study.

Investigation Number of patients (cumulative value)
At 6 weeks At 12 weeks At 18 weeks At 24 weeks
X-ray (bridging callus) 11 56 101 151
ALP (<111 IU/L) 156 151 151 151
USG-hyperechoic signal 16 64 122 151
USG- decreasing RI Not applicable 73 151 151
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3.2. Serum Alkaline Phosphatase (ALP)

ALP is a biochemical marker of bone formation (Normal level 28–111 IU/L). Average of ALP levels as measured when patients were recruited in the study was 74.03 [48,86]IU/L. ALP initially increased in all cases and reached a peak at 6 weeks. Cases of union and non-union when analysed retrospectively showed a difference in peak level of ALP in both the outcomes. Average peak level in cases of union and non-union was 97.99 [76,111] and 174 [132–190] IU/L respectively. Peak values of cases progressing to union always remained within the laboratory reference range; whereas in cases of non-union the levels recorded higher than the laboratory reference range. In cases which failed to unite the ALP levels continued to remain higher than the laboratory reference range till the end of the study period (Fig. 3). Average ALP levels at the end of the study period in united and non-union cases were 54.02 and 140.2IU/L respectively.

Fig. 3.

Fig. 3

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Serum Alkaline Phosphatase(ALP) levels.

3.3. Ultrasonography (USG)

Gray scale USG is used for qualitative assessment of echogenicity while Doppler USG is used for quantitative measurement of the Vascular Resistive Index (RI) of callus.7

3.3.1. Echogenic pattern

Significant changes in the mineral composition of callus during fracture healing changes the speed of reflected wave (echo) picked up by transducers. Based on this echo pattern, callus is labeled either as hypoechoic or hyperechoic.8 Early (soft) callus in fractures is seen as homogenous-hypoechoic callus (Fig. 4) which on mineralization matures to homogenous-hyperechoic (hard) callus (Fig. 5) over time. Fractures which fail to progressively unite show persistence of hypoechogenic pattern albeit it becomes heterogenous because of fibrosclerotic evolution in non-union. Average time taken for hyperechoic callus suggestive of mineralization in the callus to appear in uniting fractures was 15.97 [6,24]weeks. In cases which failed to unite, USG examination continued to show hypoechogenicity even at 24 weeks. With only a marginal difference, the pattern of echogenic changes with time in USG were found to complement X-ray findings during early follow-up.

Fig. 4.

Fig. 4

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USG picture showing Homogenous Hypoechogenecity.

Fig. 5.

Fig. 5

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USG picture showing Homogenous Hyperechogenicity.

3.3.2. Vascular Resistive Index

Vascular resistance index (RI), which is a measure that reflects the resistance to blood flow caused by a microvascular bed distal to the site of measurement (here around the Fracture gap/callus), was measured with Power Doppler function. Low RI is suggestive of new vessel formation, smooth blood flow and progress to union. High RI suggests resistance to blood flow and progress to non-union.9 Irrespective of the outcome, a steady elevation in RI was observed in all cases till 12 weeks. RI decreased following the elevation in patients progressing to union. In fractures failing to unite this persistently remained high even at 24 weeks (Fig. 6). Peak value of RI recorded in cases which united was 0.77 (12 weeks). Progressively RI was not recordable nearing final follow-up due to increasing thickness of cortex and decreasing number of feeding vessels of callus in cases which united. In contrast, average RI level at the final follow-up in non-union cases was 0.98 (Fig. 7).

Fig. 6.

Fig. 6

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Average Resistive Index (RI).

Fig. 7.

Fig. 7

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RI recording on USG at final follow-up in non-union.

4. Discussion

Determining fracture healing is one of the most important and basic clinical determinations made in orthopaedics. Despite numerous modalities available to assess fracture union, a combination of conventional radiography and ad-hoc clinical questions are the most common means of assessing fracture outcome. In a meta-analysis of 123 studies,10 union was defined on the basis of a combination of clinical and radiographic criteria in 62% of the articles, radiographic criteria only in 37%, and clinical criteria only in 1%. However, modalities of assessment of fracture healing should be reliable and replicable in a regular clinical setting. The objective of this study was to evaluate the role of alternative investigative methods; ALP and USG, and compare them with X-rays in monitoring the progress of treatment in diaphyseal fractures. In addition to being inexpensive and easily available, ALP and USG were selected so as to represent biochemical and physical markers of union respectively. Due to the variation in the healing of fractures of different bones and also different parts of the same bone we preferred to include only long bone fractures where the shaft was involved. We also excluded severe varieties of open fractures because of the bias that would have been created with such fractures.

Serial determination of ALP activity during fracture healing could be an additional tool in predicting fractures at risk of developing a non-union, helping the clinician to choose the appropriate intervention.11,12 Literature study shows that a stable osteosynthesis caused a small or minimum increase of ALP and callus volume, whereas those in whom a stable osteosynthesis could not be achieved, a marked increase in ALP as well as corresponding callus was observed.13,14 Muljacic et al.15 studied the changes of biochemical parameters associated with callus formation and the rate of bone healing. It was concluded by them that a major increase in the activity of these parameters in the early stages indicated formation of visible and significant callus. This increase in ALP activity observed is assumed to happen due to the rising concentration of the bone isoenzyme of Alkaline Phosphatase during the healing process16 and coincides with the initiation of mineralization.17 Although ALP levels showed a rise in fractures progressing towards union in our study, they remained within the laboratory reference range of normal limits. In cases which failed to unite the ALP levels continued to remain higher than the laboratory reference range till the end of the study period. Probably this finding reflected the stability of fixation reflecting on both outcome and ALP levels in our study.

Plain radiographs do not define union with enough accuracy and are generally inconclusive in the early stages of union.18,19 Although researchers have reported that USG is able to evaluate and predict fracture healing earlier than radiographs,20,21 USG as a tool for assessing fracture healing is not being used commonly till date. Moed et al.22 conducted a larger prospective study which showed that ultrasound findings at 6 and 9 weeks have a 97% positive predictive value and 100% sensitivity in determining fracture healing in patients with acute tibia fractures treated with intramedullary nailing. Time to determination of healing was also shorter using ultrasound (6.5 weeks) compared to nineteen-week average of radiographic data. Maffulli and Thornton23 also reported good results with the use of ultrasonography for monitoring the fracture healing process in 24 patients with long bone fractures and 3 cases of humerus non-union. The presence of a hyperechoic ultrasonographic signal from fracture site was found to have 100% correlation with the presence of hard callus on biopsy.24 In humans six distinct stages of bone healing have been reported wherein the homogenous hypoechoic area of hematoma is progressively converted to homogenous hyperechoic line representing healed cortex.25,26 151 patients in our study showed progressive conversion of hypoechoic callus to hyperechoic callus. 10 patients who did not show this conversion proved to have non-union on plain radiograph at final follow-up. With only a marginal difference, the number and pattern of echogenic changes in USG were found to complement X-ray findings during early follow-up. Thereafter echogenicity suggestive of union on ultrasound appeared quite earlier than visible callus on X-ray.

The process of fracture healing can be followed with color Doppler imaging and spectral analysis.27,28 USG is able to follow the formation of new vessels at the fracture site and to assess flow characteristics in them during development of fracture callus. In addition to following the formation of new vessels at fracture site, Doppler USG can measure RI, which is a measure that reflects the resistance to blood flow caused by a microvascular bed distal to the site of measurement. In patients with normal callus development, the caliber of afferent vessels progressively increases, their number decreases and branches appear. The RI progressively increases, up to similar values to those of nutrient vessels (0.36–0.90). Within the second month of fracture, a muscular tunic develops in the vessel wall, meaning a mature, and no longer a newly formed vessel with progressing mineralization of cortex, thus causing the RI to progressively decrease and finally disappear.17 On the other hand, patients with non-union and delayed healing have persistent higher resistance related to a poor formation of neo-vasculature and increasing peripheral resistance in residual vessels because of fibrosclerotic involution of bone healing (Graphically represented in Fig. 8). Apparently in our study, it was noted that RI steadily increased till 12 weeks in all patients; subsequently, patients who progressed to union showed decreasing RI and those who progressed towards non-union had persistently high RI even at 24 weeks. In a series of patients reported by Bottinelli O et al.29 Doppler imaging proved good to follow up the formation of new vessels at the fracture site and to demonstrate the flow characteristics in them during normal development of the callus.

Fig. 8.

Fig. 8

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Vascular changes and their temporal effect on RI in union and non-union.

A statistical evaluation of our data was ruled out due to the limited sample size. However, gross analysis of the findings of this study (Table 1) was attempted using the frequency with which all parameters i.e. X-ray, ALP, Hyperechoic callus and RI showed positive signs of union at different intervals of time. Bridging callus on X-ray, ALP levels within the laboratory reference range, hyperechoic signals on gray scale USG and a lower RI level as compared to the previous reading on Doppler USG were considered as signs indicating progress of union. A positive finding in this analysis was that the cases of each parameter were mutually inclusive of the other for that follow-up time of assessment. Hence the higher value in a column included all the cases of lesser value in the same column. Comparing all the investigations, estimation of ALP value was the earliest positive parameter showing progress towards union. X-ray and USG showed a near similar frequency of positive findings during the first three months. However, beyond 12 weeks, Hyperechogenicity on gray scale USG and serial measurement of RI on Doppler USG were found to better confirm progress in fracture union than X-rays. Non-conventional methods of assessment of fracture healing being singularly less reliable (due to a possible non-specificity), a combined evaluation of ALP and USG appear as promising investigations in assessment of the progress in fracture union. Evaluation using a combination of ALP and USG has the double advantage of reducing the total exposure to ionising radiation during the follow-up and of indicating the progress of fracture healing. However, while X-rays give qualitative information regarding the changes during fracture healing, spot measurement of ALP and USG have no defined laboratory limits for the period of follow-up after fixation, which can be used to differentiate individual cases into favourable and unfavourable categories. Nevertheless, serial examination of ALP and USG during the follow-up period would give a hint of the direction of progress in healing of the fracture. Further studies with larger sample size and uniformly included fractures are warranted to establish stronger evidence in this regard. Until then their role in monitoring outcome of fractures will still be more complimentary than supplementary to the X-rays.

Authorship declaration

All authors listed meet the authorship criteria according to the latest guidelines of the International Committee of Medical Journal Editors and all authors are in agreement with the manuscript.

Funding

There is no funding source.

Declaration of competing interest

The authors declare that there is no conflict of interest.

Contributor Information

Himanshu S. Rathwa, Email: himanshusinh60@gmail.com.

Tarun Verma, Email: tarunamiabledpv@gmail.com.

Viswanath H. Chavali, Email: vhcindia@gmail.com.

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