Rsd Medical Abbreviation

The effectiveness of neridronate for the treatment of CRPS and other bone diseases

Reflex sympathetic dystrophy (RSD) syndrome is a set of symptoms that includes severe pain, swelling, autonomic vasomotor dysfunction and reduced mobility of the affected limbs. RSD has received various names, depending on the causative factor, the country concerned or the specialty treating the patient: CRPS, Sudeck’s disease, algodystrophy, causalgia…

In 1994 the International Association for the Study of Pain (IASP) developed a unanimous definition proposing a new terminology. Thus the term complex regional pain syndrome (CRPS) type I replaced the name RSD.

 

Causes

According to the National Institute of Neurological Disorders and Stroke (NINDS), RSD is “a condition of chronic pain that is believed to be the result of central or peripheral nervous system dysfunction”. According to MedicineNet, RSD involves “abnormal irritation and excitation of nerve tissue, resulting in abnormal impulses along the nerves that affect blood vessels and skin.”

Animal studies indicate that noradrenaline, a catecholamine released from sympathetic nerves, acquires the ability to activate pain pathways after tissue or nerve injuries, resulting in MSDs. Another theory suggests that MSD, which follows an injury, is caused by activation of an immune response and symptoms associated with inflammation (redness, heat, swelling). It is believed that MSD does not have a single cause, but rather multiple causes that produce similar symptoms.

Having established that the triggering causes are still unclear, the medical profession usually refers to a group of potential causes to refer to for the diagnosis of CRPS. The most common of these are:

  • Injuries or traumas
  • Surgical Interventions
  • Degenerative arthritis of the neck
  • Shoulder problems
  • Infection
  • Brain diseases

Symptoms

RSD usually affects one of the extremities (arm, leg, hand or foot). The primary symptom of RSD is intense and continuous pain. According to the NINDS, the list of symptoms associated with MSDs includes:

 

  • Burning Pain
  • Increased skin sensitivity
  • Changes in skin temperature (hotter or colder than the opposite end)
  • Changes in skin color (spotted, purple, pale, red)
  • Changes in the structure of the skin (shiny, thin, sweaty)
  • Changes in nail and hair growth patterns
  • Rigidity and swelling in the affected joints
  • Decrease in the ability to move the affected end

Pain may extend to a larger area (i.e. from the finger to the entire arm). Emotional stress can cause worsening of symptoms.

Some experts suggest that there are three stages of RSD, during which progressive changes occur in the skin, muscles, joints, ligaments and bones of the affected area. The progression, however, has not been confirmed by clinical studies. 

In a person with RSD, damaged nerves are not able to properly regulate blood flow. In this way the body develops problems with blood vessels, bones, muscles and skin. Some people with RSD have chronic but manageable symptoms. However, a more advanced RSD can cause irreversible damage, such as muscle contractions, chronic muscle contracture (leading to limited movements), and continuous pain. The prognosis depends on when the disease is diagnosed. Without early intervention, RSD can be disabling.

 

RSD can be divided into two phases:

Phase 1

Lasts from 1 to 3 months

Severe and burning pain

Muscle spasm

Rigidity of the Rigidity of joints

Abnormal hair growth

Skin colour and temperature variations

Phase 2

Duration from 3 to 6 months

Pain that becomes more intense

Swelling

Decrease in hair growth

Nails that are cracked, brittle, grooved, spotty

Softened Bones

Rigid joints

Weak muscle tone

Phase 3

Irreversible changes in skin and bones

The pain is continuous

Muscular atrophy

Mobility severely limited

Contractions of muscles and tendons

The difficulty of diagnosis

The patient’s clinical history (signs and symptoms) is the main factor in the diagnosis of RSD. Diagnosis is made difficult because many of the symptoms overlap with other conditions.

There are no specific blood tests or other diagnostic tests for RSD. X-rays may show bone thinning (osteoporosis) and nuclear bone scans may show characteristic absorption patterns that help diagnose RSD.

Which treatment is right for each case

The common goal of each treatment is to alleviate the painful symptoms associated with RSD. It may include a considered combination of the following therapies:

  • Physical therapy and exercise
  • Psychotherapy to relieve stress, anxiety and depression
  • Sympathetic nerve blocks
  • Surgery including sympathectomy (considered controversial)
  • Spinal cord stimulation
  • Pumps for intrathecal drugs

Drugs, including topical analgesics, antiepileptic drugs, antidepressants, corticosteroids or opioids.

There is unanimous scientific consensus that priority should be given to drug treatment, which focuses on alleviating and overcoming chronic pain.

Of course, it is always preferable to support this type of treatment with other types of treatment, such as physiotherapy, a psychological support that helps the patient to accept the condition of disability and consider it only a temporary phase of his life that will be easily overcome thanks to the support of medical specialists and appropriate treatment.

Among the various drugs adopted by specialists who have been most effective is neridronate. A drug belonging to the family of bisphosphonates, neridronate is known for its effective action on bone metabolism, and it is no coincidence that it is also used to treat other bone diseases such as osteoporosis and Piaget’s syndrome.

Why choose neridronate as a treatment

It is legitimate and necessary to question which is the best cure for such a difficult and long-lasting disease, so after careful research and studies we are sure to say that the pharmacological treatment with neridronate is the best solution. The reason why neridronate is a treatment of choice against CRPS is due to its effectiveness in the treatment of bone metabolism that derives from its being part of the family of bisphosphonates not only in the case of CRPS but also for other diseases. Think of the treatment of imperfect osteogenesis, which has seen the official recognition by doctors of bisphosphonate as a basic drug after having found in a sample of young adolescents suffering from this disease which had been administered bisphosphonate, a significant improvement over three years in the mineral density of bones at the level of the lumbar spine and hip, and a reduction in the risk of fracture.

Let’s see in what terms.

Neridronic acid is a third-generation aminohexane bisphosphonate with antiresortive and anti-hypercalcemic activity. The pharmacodynamic profile is similar to that of other bisphosphonates containing nitrogen and is characterized by a high affinity for bone tissue, particularly at sites undergoing remodelling. In growing children with imperfecta osteogenesis, for example, neridronic acid rapidly increases bone mineral density measured by double radiography and this is associated with a significant decrease in the number of cumulative fractures. Similar results have been obtained in infants (under 12 months of age) and adult patients. Another pathology for which neridronic acid is used is Paget’s disease, whose patients, thanks to 200 mg of intravenous neridronic acid, are able to recover in 65% of cases, and to show a complete remission to a biochemical response (decrease > 75% of bone turnover markers) in 95% of cases.

Treatment with neridronic acid has been reported to be effective in other skeletal diseases such as osteoporosis, algodystrophy, malignancy hypercalcemia and bone metastases. Neridronic acid has been developed for parenteral use only, and is the only one used as an intramuscular injection, avoiding all limitations of oral bisphosphonates. 

Although the exact mechanism of action has yet to be fully clarified, neridronic acid binds and absorbs on the hydroxyapatite crystals in the bone matrix, thus preventing the resorption of osteoclasts. This agent binds and inhibits farnesyl pyrophosphate synthase, an enzyme that plays an important role in the path of mevalonate. This inhibits the formation of isoprenoids that are substrates for protein prenylation. This prevents the farnesylation and geranylgeranylation of proteins essential for osteoclast function, thus leading to the induction of apoptosis of osteoclasts. By preventing bone resorption mediated by osteoclasts, neridronic acid reduces the rate of bone turnover, stabilizes the bone matrix and reduces hypercalcemia.

Biphosphonates are known to be used to prevent bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma and osteogenesis deformans. Distal limb fractures cause regional bone loss with skin inflammation and pain in the injured limb that can turn into complex regional pain syndrome (CRPS). Clinical studies have reported that anti-resorption bisphosphonates can prevent fracture-induced bone loss, inhibit inflammatory cytokine serum levels, and relieve CRPS pain. Previously, we observed that inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of painful behavior in a rat’s fracture with form of CRPS, and we hypothesized that bisphosphonates could prevent painful behavior, trabecular bone loss, cutaneous upregulation of post-break cytokines and adaptive immune responses in this CRPS model.

A recent study conducted in some guinea-pigs revealed encouraging results regarding the effectiveness of bisphosphonates on bone diseases even for cases of pediatrics, as observed by some reports that testify to the effectiveness of the drug in the treatment of bone diseases.  In fact, the experiments were carried out in the following terms:

 

The rats were subjected to fracture of the tibia and immobilization for 4 weeks and were chronically administered bisphosphonates either subcutaneously perfused alendronate or oral zoledronate. Behavioural measurements included Frey’s zoledronate allodynia, non-weighting, heat and oedema. Bone microarchitecture was measured by microcalculated tomography and bone cell activity was evaluated by static and dynamic histomorphometry. Fos immunostaining of the spinal cord was performed and skin cytokine levels (tumour necrosis factor, interleukin and nerve growth factor (NGF) were determined by enzymatic immunoassay. Immunoglobulin levels of the skin and sciatic nerves were determined by enzymatic immunoassay. Rats with tibia fractures developed posterior leg allodynia, weightlessness, heat and edema, increased expression of spinal Fos and loss of trabecular bone in the lumbar vertebra and in distal bilateral femurs, measured by microcomputer tomography, increased trabecular bone resorption and osteoclastic surface with reduced rates of bone formation, increased skin inflammatory cytokine and NGF expression, and elevated immune complex deposition in the skin and nerves.

Overall, these results indicate that bisphosphonate therapy inhibits pain, osteoclast activation, trabecular bone loss and skin inflammation in the rat fracture model of CRPS, data supporting the hypothesis that bisphosphonate therapy can provide an effective multimodal treatment for CRPS.

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