Metabolic Complications Following Achilles Tendon Rupture - A Cohort Study
Condition: Achilles Tendon Rupture; Immobilization
MeSH terms: Rupture
Study type: Observational

Summary: 
      Introduction This study will evaluate the effect on glucose, lipid and bone metabolism
      following conservative orthopaedic procedures in patients who suffered from acute Achilles
      tendon rupture. The sedentary rehabilitation period following these procedures may impact
      negatively upon glucose, lipid and bone metabolic pathways whereas the more physically active
      rehabilitation period instituted 8 weeks after the injury is hypothesized to impose positive
      metabolic effects.

      The study is addition to the on-going clinical trial, Non-operative Treatment of Acute
      Achilles Tendon Rupture: Early Controlled Mobilization Compared With Immobilization,
      ClinicalTrials.gov Identifier: NCT02015364.

      Perspective This study will establish whether the well-known effects on glucose, lipid and
      bone metabolism of a sedentary lifestyle can be observed already following 8 weeks of almost
      total abstain from physical activity in non-diabetic individuals, who suffered an acute
      Achilles tendon rupture. Thereby, we will add knowledge to the previous findings following
      strict bed-rest in healthy individuals on glucose and lipid metabolism and bone turnover. In
      a clinical perspective it is important to examine the extent to which individuals deteriorate
      in various metabolic pathways to better understand the pathophysiology behind these defects
      both in healthy individuals and in patients, who undergo bed rest or an equal reduction in
      physical activity as part of their rehabilitation.

      Study design The present study includes 50 cases, who are examined early following injury (<
      2 weeks) (baseline), 8 weeks (6 - 10 weeks) after injury and 52 weeks (40 - 64 weeks) after
      injury, respectively.

      Oral glucose tolerance test (OGTT) with ingestion of 75 g of glucose during a maximum of 3
      min from baseline (0 min). Plasma for glucose, insulin, C-peptide, NEFA will be drawn.

      The individual will bring in morning spot urine for measurement of suPAR, creatinine, albumin
      and orosomucoid.

      The individual will have drawn blood for measurement of HbA1c, total cholesterol, LDL
      cholesterol, HDL cholesterol, triglyceride, Na, K, creatinine, HgB, CRP, leukocytes, ALAT,
      alkaline phosphatase, Ca++, D vitamin, TSH, albumine and amylase. Also blood for BTM and
      plasma suPAR, IL6, TNFa and hsCRP will be drawn. Finally blood for lipid density profiling
      and lipid particle size will be drawn DXA of hip and lumbar spine including abdominal
      visceral and subcutaneous fat is done on a Hologic Discovery scanner.
    

Detailed description: 
      Introduction This study will evaluate the effect on glucose, lipid and bone metabolism
      following conservative orthopaedic procedures in patients who suffered from acute Achilles
      tendon rupture. The sedentary rehabilitation period following these procedures may impact
      negatively upon glucose, lipid and bone metabolic pathways whereas the more physically active
      rehabilitation period instituted 8 weeks after the injury is hypothesized to impose positive
      metabolic effects.

      An on-going clinical trial, Non-operative Treatment of Acute Achilles Tendon Rupture: Early
      Controlled Mobilization Compared With Immobilization, ClinicalTrials.gov Identifier:
      NCT02015364 is already addressing as primary endpoints the Achilles tendon total rupture
      score and patient reported validation score developed to assess symptoms and physical
      activity after treatment for Achilles tendon rupture. The present study is an
      amendment/extension of that ongoing clinical trial.

      An oral glucose tolerance test (OGTT) with frequent measurements of glucose, insulin,
      C-peptide and plasma free fatty acids can provide detailed information on insulin
      sensitivity, glucose tolerance, beta cell function, lipolysis and lipid oxidation as well as
      metabolic clearance of insulin(11-13).

      Modern DXA scanners exhibit high performance and sensitivity to distinguish small changes in
      BMD. Also sensitive markers of changes in bone metabolism have recently been available. In
      particular two bone mass turnover markers (BTM) have been suggested to monitor bone
      resorption (CTX, carboxy-terminal cross-linked telopeptides of type 1 collagen) and bone
      formation ( P1NP, procollagen type 1 amino-terminal propeptide(14), but also osteocalcin (OC)
      is suggested as a marker of bone formation. DXA scanners have recently been validated to
      measure visceral adiposity, which is strongly associated with insulin sensitivity(15). A DXA
      scan exposes the individual to an X-ray radiation equal to only one day of background
      radiation, which makes this scanning modality much less harmful in terms of radiation dose
      compared to traditional CT scans (a 100-fold less radiation).

      Traditional markers of low grade inflammation (LGI) include TNFa and IL6 and hsCRP. New
      promising markers include suPAR in plasma and urine and urine orosomucoid. suPAR has shown to
      predict CVD in non-diabetic community resting individuals(16). Urine orosomucoid is a strong
      predictor of major events in T2D and might be an early marker of glucose metabolic
      derangement(17). Low density lipoprotein (LDL) particles and especially those with a low
      particle size are atherogenic(18). Thus increased levels of LGI markers and immune markers
      including small LDL particles exhibit a particular at herogenic cocktail. A sedentary
      lifestyle is associated with an increase in these markers of LGI, impaired immune response
      and dyslipidaemia.

      In the present setting we want to investigate the putative negative impact on glucose, lipid,
      and bone metabolism during a period of restrain from exercise secondary to immobilization
      following Achilles tendon rupture. We also want to study these patients during their physical
      active rehabilitation (at week 8 - 52), to establish whether they succeed in improving the
      metabolic impairments they suffered during the early post-injury period, during which period
      strong limitations in physical activity is prescribed (week 0 - 8).

      Perspective This study will establish whether the well-known effects on glucose, lipid and
      bone metabolism of a sedentary lifestyle can be observed already following 8 weeks of almost
      total abstain from physical activity in non-diabetic individuals, who suffered an acute
      Achilles tendon rupture. Thereby, we will add knowledge to the previous findings following
      strict bed-rest in healthy individuals on glucose and lipid metabolism and bone turnover. In
      a clinical perspective it is important to examine the extent to which individuals deteriorate
      in various metabolic pathways to better understand the pathophysiology behind these defects
      both in healthy individuals and in patients, who undergo bed rest or an equal reduction in
      physical activity as part of their rehabilitation.

      Hypothesis Implementation of a sedentary lifestyle with almost no physical activity in
      non-diabetic individuals undergoing non-operative treatment of acute Achilles tendon rupture
      will during 8 weeks

        -  impair insulin sensitivity and glucose effectiveness

        -  decrease disposition index

        -  compensatory decrease in insulin clearance

        -  decrease lipid oxidation

        -  increase visceral adipose tissue

        -  increase number of low density lipoprotein particles and a decrease the particle size

        -  increase immune and low grade inflammatory response as measured in plasma and urine

        -  induce bone loss in hip as measured by BMD

        -  increase bone resorption and decrease bone formation as measured by selected bone
           turnover markers.

      During the following physical active rehabilitation from week 8 to week 52 the above proposed
      negative impact upon glucose, lipid and bone metabolism is thought to reverse at least partly
      so.

      The relative positive effect on metabolic performance is hypothesized to be associated with
      duration from immobilization to full mobilization, which will be monitored by use of
      validated tools.

      Study design Fifty non-diabetic individuals of age 18 to 70 years who should undergo
      non-operative treatment of acute Achilles tendon rupture and who are included to the
      randomized clinical trial: Non-operative Treatment of Acute Achilles Tendon Rupture: Early
      Controlled Mobilization Compared With Immobilization, ClinicalTrials.gov Identifier:
      NCT02015364 at the department of orthopaedics, Hvidovre Hospital are recruited as cases for
      this study. That study examines the effect on functional outcome measures of early controlled
      mobilization of the ankle from the beginning of week 3 following injury versus full
      immobilization during the initial 8 weeks post injury. Both groups are allowed full
      weight-bearing from the beginning of week 3 and physical activity level is expected to be the
      same in the two groups. As such randomization regime is unlikely to influence metabolism.

      The present study includes 50 cases, who are examined early following injury (< 2 weeks)
      (baseline), 8 weeks (6 - 10 weeks) after injury and 52 weeks (40 - 64 weeks) after injury,
      respectively.

      Examinations Oral glucose tolerance test (OGTT) with ingestion of 75 g of glucose during a
      maximum of 3 min from baseline (0 min). Plasma for glucose, insulin, C-peptide, NEFA will be
      drawn at time -10, -5, -1, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120, 150, 180, 240 min. This
      test will be performed in the morning starting at approximately 8 am. The tests are done
      after an overnight fast of at least 10 hours.

      The individual will bring in morning spot urine for measurement of suPAR, creatinine, albumin
      and orosomucoid.

      Before the OGTT the individual will have drawn blood for measurement of HbA1c, total
      cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, Na, K, creatinine, HgB, CRP,
      leukocytes, ALAT, alkaline phosphatase, Ca++, D vitamin, TSH, albumine and amylase. Also
      blood for BTM and plasma suPAR, IL6, TNFa and hsCRP will be drawn. Finally blood for lipid
      density profiling and lipid particle size will be drawn before the OGTT.

      Body weight and height and waist and hip circumference will be measured. DXA of hip and
      lumbar columna including abdominal visceral and subcutaneous fat is done on a Hologic
      Discovery scanner by use of updated software. DXA will be carried out approximately at 12 am.

      Acquisition of glucose and lipid metabolism will be done by use of the MinModel and the NEFA
      MinModel as described (11;12) All blood and urine samples will be destroyed after analysis.
      However a research biobank will be established since the period of time from most blood and
      urine sampling until analysis exceeds 1 week. This study will store all urine and blood
      samples in a freezer until all case subjects and controls have finished examinations. The
      duration of this period will be maximum 2 years from last patient last visit. Thus the
      research biobank will be established for storage only.

      The urine and blood samples will be destroyed after analysis at Hvidovre and Glostrup
      Hospitals. Analysis results will all be anonymous and some will be sent abroad to our
      researcher Prof. Raymond Boston in USA, who will perform statistical calculations from
      analysis data. Permission for establishment of a research biobank is obtained from the Danish
      Data protection Agency.

      Measurements of physical activity are acquired from the Primary Investigators ongoing trial
      "Non-operative Treatment of Acute Achilles Tendon Rupture: Early Controlled Mobilization
      Compared With Immobilization".

      Statistics Ten days of bed rest in 13 healthy young individuals showed a 20% (P<0.05)
      significant decrease in insulin sensitivity and a 50% (P<0.05) reduction in lipid
      oxidation(2). Thirty-one days of bed rest in 8 healthy women was significantly associated
      with bone loss in total hip (2.07%, P<0.001)(7).

      The present study does not imply strict bed rest but exhibits a longer sedentary period of
      following up compared to the above studies and include a larger number of participants, also.
      During the initial 8 weeks of strictly sedentary immobilization following the injury of the
      Achilles tendon we suggest that the patients will decrease their insulin sensitivity by at
      least 20%, the estimate of SD of the endpoint is 20%. Thus, using the MIREDIF statistics
      (Douglas Altman, Practical statistics for Medical research, Chapman & Hall, 1999), we can
      calculate that a population of 22 patients will generate a power >90% at significance level
      P<0.05 to investigate that primary endpoint. Similarly, the SD on lipidoxidation is 30% and
      the estimate is that the change during the sedentary period is at least 30%, thus by n=22
      patients the power will be > 90%. Finally the change in BMD is likely 1% and the SD is 1%,
      thus n=22 patients will provide a statistical power of at least 90%. During the period of
      physical restitution we estimate a fully reversion of the deficit in endpoints during the
      sedentary period, i.e. similar calculation on power is valid during the restitution period.

      The participants in the present study are included from the randomized clinical trial:
      Non-operative Treatment of Acute Achilles Tendon Rupture: Early Controlled Mobilization
      Compared with Immobilization. Randomization regime is unlikely to influence metabolism,
      however, it will be considered as a variable in the statistical analyses of the endpoints.

      Ethical issues The study adheres to the Danish Act on Processing of Personal Data and, Danish
      Act on Health and the Helsinki II convention of clinical trials. All participants are
      informed about the purpose of the study and all ethical issues and a written consent is
      obtained before participation. At any given time, the participants can withdraw their
      acceptant for participation in the study. Personal data concerning demographic relations such
      as gender and age will be accessed as well to ensure the case subjects meet the inclusion
      criteria and for statistically use. To make assessments on study participation, the principal
      investigator will also gain access to relevant data from the patients medical files
      concerning illnesses or conditions the case subject might report.

      The amount of blood drawn during the 52 weeks of participation in the study is less than 500
      ml, which is the standard amount of blood drawn at a single donation of blood from a blood
      donor. The use of intravenous cannula can cause irritation or infection of vein or insertion
      site. All procedures will be performed as described in SOP.

      The X-ray radiation from DXA during the study period equals 3 days of background radiation in
      Denmark and this amount of radiation is 30-fold less than that of a standard CT-scan of
      abdomen. In other words the dose of radiation is so low that a calculation of risk is not
      possible.
    

Intervention name(s): Immobilization due to an Achilles tendon rupture
Intervention type(s): Other
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Fifty non-diabetic individuals of age 18 to 70 years who should undergo non-operative
        treatment of acute Achilles tendon rupture and who are included to the randomized clinical
        trial: Non-operative Treatment of Acute Achilles Tendon Rupture: Early Controlled
        Mobilization Compared With Immobilization, ClinicalTrials.gov Identifier: NCT02015364 at
        the department of orthopaedics, Hvidovre Hospital are recruited as cases for this study.
      
Biospecimen description: 
      Blod and urine samples
    
Keywords: Metabolism; Bone metabolism; Glucose Metabolism; Lipid metabolism; Low grade inflamation