Clinical trial NCT02023411
Conditions: Diabetic Neuropathic Arthropathy
Keywords: Teriparatide Inactive Charcot's neuroarthropathy
Sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh
Start date: 2014-01-01; Completion date: 2018-12-01
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Diabetic foot represents a major medical , social and economic problem worldwide.

Charcot's neuroarthropathy, being a common cause of diabetic foot, has been an intriguing topic of research for endocrinologists, podiatrists and surgeons. After its first description by JEAN-MARTIN CHARCOT in 1868, many theories have been put forward regarding its pathophysiology , but not much research has been done for its prevention and treatment , specially the inactive stage.

The course of Charcot 's neuroarthropathy is triphasic , with the diagnosis being usually missed in the active stage, henceforth the patients often come to us with a deformed foot. As a consequence , the osteoclastic activity in active stage renders the foot bones demineralized and weak, thus being susceptible to fracture and fragmentation.

Teriparatide is recombinant human (1-34) parathyroid molecule that has been approved for post-menopausal osteoporosis and in men with primary or secondary osteoporosis. It acts by preferentially stimulating osteoblast over osteoclast activity resulting in new bone formation and an increase in the rate of bone remodeling which manifest as an increase in skeletal mass and bone mineral density .

Keeping the pathophysiology of Charcot's foot in mind, teriparatide may be used as potential treatment for inactive Charcot's neuroarthropathy but there are no studies or randomized trials in this setting, till date. We hypothesize that teriparatide may increase the remodeling of foot bones in Charcot's neuroarthropathy, improve bone mineral density, subsequently leading to a reduction in the risk of fractures and progression of deformities. This study plans to compare the effects of teriparatide in diabetes patients with inactive Charcot's foot in a placebo controlled design.

Detailed description:
Charcot neuroarthropathy (CN) was first described by Jean-Martin Charcot in a patient with tabes dorsalis who recognized that peripheral neuropathy could lead to neuropathic joints. This condition has many names, including Charcot osteoarthropathy, neuropathic osteo- arthropathy, and many others. Charcot foot may occur as a complication of neurosyphilis, syringomyelia, leprosy, poliomyelitis, congenital neuropathy and diabetes mellitus , the latter currently being the most common cause of CN. Since the description of CN in 1883, its pathophysiology remains an enigma, and there are no strict guidelines for the treatment of this disorder.

India has more people living with diabetes than any other country of the world and diabetic foot is one of the common diabetic complications found in India. The prevalence of Charcot foot in diabetes is not clearly known (0.1% to nearly 30%), but it is now appreciated that the condition is not as infrequent as might be generally thought. CN is characterized by progressive destruction of bones and joints of the foot with accompanying osteopenia. The current belief is that once the disease is triggered in a susceptible individual, it is mediated through a process of uncontrolled inﬂammation in the foot. This inﬂammation leads to osteolysis and is indirectly responsible for the progressive fracture and dislocation that characterizes its presentation.

The pathophysiologic event is cytokine- driven elevation of the receptor activator of nuclear factor kappa B ligand (RANKL), which, in turn, enhances the synthesis of nuclear factor kB (NF-kB). The latter promotes osteoclast maturation and osteoclastic activity, leading to osteoporosis in the affected bones. In parallel , NF-kB enhances the production of osteoprotegerin from osteoblasts, in order to provide an antagonist of RANKL and mitigate its effects. Ultimately, the cascade of all pathophysiologic changes leads to the development of the Charcot's foot and demineralization of bones.

If the condition is correctly diagnosed and the patient is appropriately immobilized, the local inflammation will subside and further bony destruction including progressive loss of mineral density may be prevented. But the diagnosis of CN is frequently missed in the active phase in almost 25% of cases. In the inactive stage, signs of local inﬂammation progressively recede, redness subsides, and the difference in skin temperature between the two feet diminishes. Most of the patients coming to our diabetes clinic present in the inactive phase with stable foot deformities viz rocker bottom deformity, loss of longitudinal or transverse arches, bony prominence (medial convexity) and significant demineralization of bones. These foot deformities result in abnormal high-pressure areas that are particularly prone to ulceration; a consequence of continued weight bearing.

Recombinant human parathyroid hormone fragment (teriparatide) is an anabolic therapy , that preferentially stimulates osteoblast over osteoclast activity resulting in new bone formation and an increase in the rate of bone remodeling. These effects manifest as an increase in skeletal mass, bone mineral density (BMD) and bone strength, subsequently leading to a reduction in the risk of fractures. It has been well established that teriparatide increases bone remodeling in the skeleton through histomorphometry studies and measurements of bone turnover markers (BTM), and recently direct measurements of the effect of teriparatide on the site-specific metabolic activity of the skeleton has been shown in patients of osteoporosis.

Radionuclide bone scan imaging using the radiopharmaceutical 99Technetium-methylene diphosphonate (MDP) has a useful role in both clinical practice and research to investigate metabolic bone diseases and response to treatment. In clinical practice, bone scans are reported solely on a qualitative visual interpretation of images allowing for the detection of discrete changes in the skeleton in areas of focal tracer uptake. An increased 99mTc-MDP skeletal uptake with teriparatide is seen in patients with osteoporosis indicating an increased bone formation which was supported by BTM increases. Recently, quantitative bone scintigraphy with MDP is described as a more sensitive tool to study the bone-remodeling process even in CN. The potential utility of quantitative bone scanning for the diagnosis and more importantly for CN activity is suggested. However, translating visual assessments into quantitative data with F18 PET/ SPECT CT to study the regions of interest (ROI) and assess the response to teriparatide will be more specific.

The role of teriparatide in diabetes patients with CN has not been studied, till date. Keeping the pathophysiology of CN in mind, the present study plans to assess the efficacy of teriparatide in chronic CN by studying the change in bone remodeling as quantitated by F18 SPECT CT, BMD and markers of bone turnover. We will also assess the benefits of teriparatide, if any, on the foot morbidity i.e incidence of fractures, progression of deformity or need for amputation over the follow up period of 18 months.

Arms: arm 1: 10 diabetic patients with inactive Charcot's foot who are calcium and Vit.D sufficient will receive 20 microgram of teriparatide , subcutaneous between 8-9 p.m., daily. arm 2: 10 diabetic patients with inactive Charcot's foot who are calcium and Vit.D sufficient will receive placebo , subcutaneous between 8-9 p.m. , daily.
Interventions: intervention 1: Teriparatide intervention 2: Placebo
Intervention descriptions: intervention 1: recombinant human parathyroid hormone (1-34) subcutaneous every day at 8-9 pm intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
To Study the Efficacy of Teriparatide in Improving Remodeling of Foot Bones in Chronic 
Charcot Neuroarthropathy in Patients With Diabetes Mellitus. 
Protocol date: 1/1/2016 
NCT : ABAR-1072013 
 
Patients and methods:  
People with type 2 diabetes and inactive charcot neuroarthropathy of foot attending the 
diabetic foot care unit of department of endocrinology at Post Graduate Institute of Medical 
Education and Research (PGIMER), Chandigarh were prospectively enroled in the study. An 
informed and written consent was obtained from all the participants and the Institute Ethics 
Committee approved the study protocol. The diagnosis of inactive charcot foot was 
confirmed on clinical and radiological examination (Eichenholtz’s classification) (16) of the 
foot. The inactive charcot foot was suggested by the absence of signs of activity i.e lack of 
temperature difference between two feet (measured using infrared thermometer) and no T2 
hyperintensity on Magnetic resonance imaging (MRI) and/or the presence of deformities like 
pes-planus or rocker bottom foot with a prior history of active charcot neuroarthropathy (12 
months prior) or scrutiny of treatment records revealed active charcot foot (total contact cast) 
in recent past. The patients with active charcot neuroarthropathy (within 12 months), active 
on inactive charcot neuroarthropathy, osteomyelitis of foot bones, concurrent peripheral 
vascular disease, presence of non-healing ulcer or a history of foot ulcer in the past 12 weeks, 
presence of vascular calcification on foot X-ray, osteoporosis at lumbar spine or hip (defined 
as T Score≤ -2.5), renal failure (eGFR<60 ml/min), previous/prevalent bone malignancy, 
previous malignancy with metastasis to bone, received teriparatide or bisphosphonates earlier 
(within past 12 months), primary hyperparathyroidism, pregnant women were excluded from 
the study. Patients were randomized by computerized random program into two groups to 
receive Teriparatide (T group) 20 μg between 8-9 pm or placebo (P group) subcutaneous 
daily. The clinician in-charge, the participants, radiologist and the nuclear medicine 
specialists were unaware of the treatment group allocation. The adherence to teriparatide or 
placebo was ensured by telephonic call and collecting empty cartridges on subsequent visits  
from the participants. The standard treatment for inactive charcot neuroarthropathy by advice 
for effective offloading with modified footwear were provided to all patients.  
The affected foot was divided into three regions of interest (ROI) depending upon the site of 
involvement as per Sanders and Frykberg radiological grade (17). The forefoot (R1) included 


the foot proximal to tarso-metatarsal (TMT) joint; mid-foot (R2) included the TMT joint and 
the tarsal bones; and hind foot (R3) included the talus, calcaneum, talo-calcaneal and the 
ankle joint. The clinical details pertaining to diabetes, glycemic status, presence of micro 
vascular and macrovascular complications were recorded including the local examination of 
the foot. Measurements of serum calcium, alkaline phosphatase, creatinine, parathyroid 
hormone iPTH(1–84)] and 25- hydroxy vitamin D were performed at baseline, 3 months and 
12 months. Samples for bone turnover markers i.e P1NP and CTx were collected in the 
morning after overnight fast at 0, 3 and 12 months and measured with 
electrochemiluminescence immunoassay (ECLIA) on COBAS600 (Roche, Germany) [PINP, 
Orion Diagnostica, Espoo, Finland; interassay coefficient of variance (CV) 3.1–8.2%and 
CTX with Ostex, Seattle, WA USA; interassay CV 6.7–14.8% kits].  
Radiological Work-up:  
Weight bearing foot radiograph (antero-posterior and lateral) were obtained for the 
calculation of calcaneal inclination angle (CIA), talar declination angle (TDA), angle of 
medial longitudinal arch (ALA) and lateral talo-calcaneal angle (TCA). Calcaneal inclination 
angle was calculated by the angle formed at the intersection of the line drawn from the 
anterior inferior calcaneal border of the calcaneo-cuboid articulation and another line from 
the calcaneum to the 5th metatarsal. Talar declination angle formed between the line 
representing the talar axis and a line representing plantar surface of the calcaneum to the 5th 
metatarsal. Angle of medial longitudinal arch  
5th metatarsal. Lateral talo-calcaneal  
is drawn between the calcaneal inclination 
axis and a line drawn along the inferior edge of the 
 
was defined as the angle between the mid-talar axis and calcaneal inclination axis. 
angle  
Bone mineral density (BMD) measured in gm/cm2of the foot as a whole and individually at 
the region of interest (ROI) was performed on DXA (Hologic Inc., Bedford, MA, USA) at 


baseline and 12 months. The software used for the vertebral BMD was applied for the foot 
BMD and reproducibility was assessed by three repeated measurements.  
Nuclear Imaging:  
Regional 18F-PET/CT images of the feet were acquired at baseline, 3 and 12 months using a 
dedicated PET/CT scanner (Discovery STE16 or 710, GE Healthcare, Milwaukee, WI, USA) 
in 3-D mode at 1, 2 and 3 hours after intravenous injection of 185MBq (5mCi) of Na18F- 
fluoride. The CT variables for acquisition were 140kV, 40mA & pitch of 1.375:1. 
Reconstructed trans-axial, coronal and sagittal images were viewed on advantage workstation 
adw 4.6. Semi quantitative analysis for standardized uptake value (SUVmax) was done by 
drawing the ROIs at the fore, mid and hind foot regions and compared with the baseline 18F- 
PET/CT for change in SUVmax. Increased tracer uptake in the fore, mid and hind foot in 
relation to the background normal bone was taken as abnormal. A SUVmax ≥ 2.5 at 2 hours 
was considered significant based on our prior experience [15].  
Outcome Measure:  
Primary outcome measure was the change in SUVmax on 18F-PET/CT compared to baseline. 
Bone turnover markers, foot BMD (ROI) and foot inclination angles were the exploratory 
variables.