Efficacy of Teriparatide in Diabetic Inactive Charcot Neuroarthropathy of Foot
Condition: Diabetic Neuropathic Arthropathy
MeSH terms: Arthropathy, Neurogenic
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Teriparatide; Placebo
Intervention type(s): Drug; Other
Intervention description(s): recombinant human parathyroid hormone (1-34) subcutaneous every day at 8-9 pm; Placebo
Other intervention name(s): parathyroid hormone; recombinant human parathyroid hormone
Intervention MeSH terms: Teriparatide; Hormones; Parathyroid Hormone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Teriparatide; Inactive Charcot's neuroarthropathy