ON CALCIUM METABOLISM AND OSTEOPOROSIS

Symptoms And Treatment of Osteoporosis:

Most of the body Calcium (Ca++) is extracellular (in serum) in ionized form. Ca++ is extremely important for maintaining: Skeletal metabolism, nerve, and muscle function and cell activity. The intracellular Ca++ functions as cytoplasmic second – messenger and moves in and out of the cell membrane through the Calcium channels. The normal Calcium serum levels is 8.5 to 10.5 mg/dl around 40 % of circulating Calcium is bound to proteins (Albumin 90%) and as anions, such as Phosphate, Citrate and Sulfate. The extracellular Calcium is tightly regulated by HORMONES and its concentration is indirectly affected by the Parathyroid  (PTH) hormone, by stimulating the renal reabsorption.

How is the extracellular Ca++ metabolized?

  • From the daily Calcium intake of 1000 mg, 100 mg are excreted in feces and 200 mg in urine. From the guts some 300 mg are absorbed and moved to the Calcium pool mediated by Vitamin D and from this pool 100 mg a re moved back to the guts again for excretion Likewise from the Calcium pool, 8800 mg are reabsorbed by the kidneys and 200 mg are excreted in urine. In addition, 200 mg are moved from the skeleton to the Calcium Pool mediated by the PTH and also 200 mg are reabsorbed back by the bones.
  • Calcium deficiency can be produced by physical inactivity, immobilization, and certain environment like the astronauts subjected to prolonged lack of gravity.
  • Calcium intestinal absorption may also be reduced in certain diseases such as: chronic diarrhea, malaria absorption conditions, rapid intestinal transit, use of steroids or Phenytoin treatment of Epilepsy

CALCIUM MAINTENANCE AND REPLACEMENT

The FDA daily allowance is 1000 mg/d in adults less than 50 y, 1200 mg\d for those more than 50 y and 1300 mg\d  for healthy adolescents. More than 99% of total body calcium is sequestered in bones and teeth.

HYPER CALCEMIA

Hypercalcemia is the result of: 

  • Increased skeletal re sorption
  • Increased intestinal absorption
  • Increased PTH activity

The main signs and symptoms of primary Hyperparathyroidism are: fatigue, weakness ,  thirst, frequent urination, calcium kidney stones formation ,  hematuria, bone loss (osteoporosis), joint pain, bone pain, loss appetite, heartburn, acid  gastric reflux , peptic  ulcer disease, chronic  constipation, low mental concentration, forgetfulness and mental depression. The most common cause of hypercalcemia in hospitalized patients is CANCER. Malignancy may occur due to increased secretion of PTH activity or due to bone meta Stasis. Hypercalcemia may also result for increase in Calcium production in certain diseases such as: Sarcoidosis, tuberculosis, crohn”s disease, and lymphomas. For which the best treatment is with glucocorticoides (Prednisolone and hydrocortisone) Otherwise the treatment of hypercalcemia, in general, are Biphosphonates Intravenously. Examples of Biphosphonates are Pamidronates (Aradia) and Zoledronic acid (Zometa).

HYPOCALCEMIA

Hypocalcemia is calcium deficiency in those cases with calcium serum level < than 8.5 mg/dl. The treatment for acute hypocalcemia is CALCIUM GLUCONATE IV, 10% solution, containing 9.3 mg Ca/ ml. Dose 10-15 mg/kg of body wt. over 4-6 hours. For faster infusion use l0mI of 10% solution diluted in 50 ml of 5% dextrose in water (D 5 W) over 5 minutes. For Hypocalcemic TETANY or laryngospasm: CALCIUM CHLORIDE (CaCl) is given. 10% solution containing 1.36 mEq Ca2++/ ml, IV at rate of less than 1 ml/minute to prevent cardiac arrhythmia.

Caution:  Calcium Gluconate may give a generalized burning sensation due to vasodilation, which also can lead to arterial hypotension. The alternate treatment is CALCIUM GLUPECTATE 22% solution, containing 18 mg Ca2++/ml in a volume of 5-20 ml IV for severe Tetany. Mild and chronic hypocalcemia can be treated with oral calcium and vitamin D combination. Oral Calcium preparation are Calcium Carbonate, Citrate, Phosphonate, Lactate, and Gluconate in doses of 1-2 G/day up to 3-6 G /day.

 

TREATMENT AND PREVENTION FOR OSTEOPENIA OR OSTEPOROSIS.

 CALCIUM CARBONATES

ACTONEL (Risedronel Sodium). ACTONEL is a biphosphonate, it is available in tabs 5, 30, 35, 75 and150 mg once a week dose packs. Dose as follows: 5mg/day, 35 mg/week, or 75 mg /day for 2 days once a month or 150 mg once a month. Actonel and other biphosphonates are indicated both for treatment or prevention of Osteoporosis in menopausal, postmenopausal females as well as Osteporosis in males. ACTONEL is also available as ACTONEL PLUS CALCIUM as a blister package containing 28-day course therapy per wee k as follows: #4 ACTONEL 35 mg tablets for the first day and # 24 Calcium Carbonate 1250 mg tablets for days 2 to 7h. Either kind of ACTONEL, for the first day dose has to be taken with Sounces of plain water, 30 minutes before the first meal or drink of the day. Another biphosphonate is BONIVA (Ibandronate). In general the biphosphonates act as inhibitors of osteoclasts-mediated bone resorption thus inducing osteoblast activity to favor bone mass. The recommended dose of BONIVA is 100-150 mgs once a month or 2.5 mg per day along with 400 IU of Vitamin D3 plus 500 mg of Calcium. Dose of 2.5 mg a day reduces the incidence of second bone fracture. Another biphosphonate is FOSAMAX ( Alendronate) available in tablets 5, 10, 35 and 70 mgs. It is also available as FOSAMAX PLUS VIT D3, strengths 7Omg/ 2800 IU and 7Omg/5600 IU tabs. The recommended dose is one tablet once a week or 10 mg tabs per day.

CALCIUM ACETATE

Phospho-LO gel caps 667 mg. Mostly indicated in concomitant hyper phosphatemia in end-stage renal failure (dyalisis). Dose: 2 gel caps with each meal.

CALCIUM CITRATE (Active Ca). Usually mixed with Vitamin D3, Vitamin K, Mg 100 mg and calcium 200mg. Take 4 tabs/day with meals.

OTHER TREATMENTS:

Calcitonin, Calcitriol and Genestein aglycone.

  • MIACALCIN (Calcitonin-Salmon) Calcitonin is a polypeptide hormone secreted by cells of the Thyroid gland. When provided reduces calcium in serum and reduces and reduces calcium bone resorption. It is used both in hypocalcaemia and postmenopausal osteoporosis. Dose for the latter 100 IU subcutaneous or IM every other day. Simultaneous give Calcium Carbonate 105 Gm and Vit D 400 IU per day. MIALCALCIN is also available as Nasal Spray, one spray (200 IU) per day. Monitor effectiveness of treatment with periodic lumbar vertebral bone density studies, also periodic analysis of serum Calcium, Magnesium and Alkaline Phosphatase levels, and also 24 hours urinary calcium and phosphates levels.
  • RECALTROL (Calcitriol) Occurs naturally in humans. It is the active form of Vitamin D3 (cholecalciferol).
  • FOSTEUM (Genestein Aglycone). It is given as a dietary management of metabolic process of Osteopenia and Osteoporosis. Genetein is obtained from soy, citrated zinc and cholecalciferol (Vit D3).

Mild hypocalcemia is usually asymptomatic. Moderate to severe hypocalcemia usually presents as: Tingling sensation, paresthesias, cramps, increased neuromuscular excitation, tetany, laringospasm, and even tonic-clonic seizures. If low calcium is concomitant to low PTH activity the symptoms may include: Total body hair loss (alopecia totalis) starting in infancy, grooved finger nails, cataracts, brain basal ganglia calcifications, mental depression, chronic anxiety, and delusions. Hypocalcemia may also be present in Vitamin D deficiency, poor nutrition, starvation, and mal absorption disorders. Some cases of chronic hypocalcemia in adults may follow thyroid gland surgery or radiation.

CALCIUM AND PHOSPHATE METABOLISM

Calcium and phosphate homeostasis is regulated by PTH and 1,25 dihydro Vitamin D (Calcitriol) through the effects of the kidneys, the intestines and the PTH gland. The l,25 dihydro Vitamin D is the only active Vitamin D. It is formed from the inert 25 OH vitamin D3, which is stored in fat tissue as a reserve.

VITAMIN D

Vitamin D is critical to preserve bones but it is also important to protect the body from certain diseases like cancer s of the Prostate, Breast and Colon, also other conditions like Non-Hodgeking Lymphoma, Rheumatoid Arthritis, Type II Diabetes, Macular Degeneration, Multiple Sclerosis (MS), Fibromyalgia, Gingivitis and others. It also promotes the efficiency of the immune system, regulates the cell growth, and has also anti-inflammatory properties. There are basically two kinds of Vita min D: From animal source, CALCIFEROL (Vitamin D3, and from plants source, ERGOCALCIFEROL (Vita min D2). Vitamin D is soluble in fat just as Vitamin A, Vitamin E, and Vitamin K are. The normal, recommended daily dose is 800-1000 international units (IU). The major natural sources of Vitamin D are fish, especially Salmon, Tuna, Sardines, Mackerel, and Cod Liver. The following are the people more at risk for Vitamin D deficiency: Older adults, people with limited sun exposure, the use of skin screen products, fair skin (less melanin), some mal absorption diseases such as Crohn’s , pancreatic deficiency, cystic fibrosis, sprue, liver diseases and post gastric by-pass surgery.

ON CALCIUM METABOLISM AND OSTEOPOROSIS

Symptoms and Treatment Of Osteoporosis:

Most of the body Calcium (Ca++) is extracellular (in serum) in ionized form. Ca++ is extremely important for maintaining: Skeletal metabolism, nerve, and muscle function and cell activity. The intracellular Ca++ functions as cytoplasmic second – messenger and moves in and out of the cell membrane through the Calcium channels. The normal Calcium serum levels is 8.5 to 10.5 mg/dl around 40 % of circulating Calcium is bound to proteins (Albumin 90%) and as anions, such as Phosphate, Citrate and Sulfate. The extracellular Calcium is tightly regulated by HORMONES and its concentration is indirectly affected by the Parathyroid (PTH) hormone, by stimulating the renal reabsorption.

How is the extracellular Ca++ metabolized?

• From the daily Calcium intake of 1000 mg, 100 mg are excreted in feces and 200 mg in urine. From the guts some 300 mg are absorbed and moved to the Calcium pool mediated by Vitamin D and from this pool 100 mg a re moved back to the guts again for excretion Likewise from the Calcium pool, 8800 mg are reabsorbed by the kidneys and 200 mg are excreted in urine. In addition, 200 mg are moved from the skeleton to the Calcium Pool mediated by the PTH and also 200 mg are reabsorbed back by the bones.

• Calcium deficiency can be produced by physical inactivity, immobilization, and certain environment like the astronauts subjected to prolonged lack of gravity.

• Calcium intestinal absorption may also be reduced in certain diseases such as: chronic diarrhea, malaria absorption conditions, rapid intestinal transit, use of steroids or Phenytoin treatment of Epilepsy

CALCIUM MAINTENANCE AND REPLACEMENT

The FDA daily allowance is 1000 mg/d in adults less than 50 y, 1200 mg\d for those more than 50 y and 1300 mg\d for healthy adolescents. More than 99% of total body calcium is sequestered in bones and teeth.

HYPER CALCEMIA

Hypercalcemia is the result of:

• Increased skeletal re sorption

• Increased intestinal absorption

• Increased PTH activity

The main signs and symptoms of primary Hyperparathyroidism are: fatigue, weakness , thirst, frequent urination, calcium kidney stones formation , hematuria, bone loss (osteoporosis), joint pain, bone pain, loss appetite, heartburn, acid gastric reflux , peptic ulcer disease, chronic constipation, low mental concentration, forgetfulness and mental depression. The most common cause of hypercalcemia in hospitalized patients is CANCER. Malignancy may occur due to increased secretion of PTH activity or due to bone meta Stasis. Hypercalcemia may also result for increase in Calcium production in certain diseases such as: Sarcoidosis, tuberculosis, crohn”s disease, and lymphomas. For which the best treatment is with glucocorticoides (Prednisolone and hydrocortisone) Otherwise the treatment of hypercalcemia, in general, are Biphosphonates Intravenously. Examples of Biphosphonates are Pamidronates (Aradia) and Zoledronic acid (Zometa).

HYPOCALCEMIA

Hypocalcemia is calcium deficiency in those cases with calcium serum level < than 8.5 mg/dl. The treatment for acute hypocalcemia is CALCIUM GLUCONATE IV, 10% solution, containing 9.3 mg Ca/ ml. Dose 10-15 mg/kg of body wt. over 4-6 hours. For faster infusion use l0mI of 10% solution diluted in 50 ml of 5% dextrose in water (D 5 W) over 5 minutes. For Hypocalcemic TETANY or laryngospasm: CALCIUM CHLORIDE (CaCl) is given. 10% solution containing 1.36 mEq Ca2++/ ml, IV at rate of less than 1 ml/minute to prevent cardiac arrhythmia.

Caution: Calcium Gluconate may give a generalized burning sensation due to vasodilation, which also can lead to arterial hypotension. The alternate treatment is CALCIUM GLUPECTATE 22% solution, containing 18 mg Ca2++/ml in a volume of 5-20 ml IV for severe Tetany. Mild and chronic hypocalcemia can be treated with oral calcium and vitamin D combination. Oral Calcium preparation are Calcium Carbonate, Citrate, Phosphonate, Lactate, and Gluconate in doses of 1-2 G/day up to 3-6 G /day.

TREATMENT AND PREVENTION FOR OSTEOPENIA OR OSTEPOROSIS.

CALCIUM CARBONATES

ACTONEL (Risedronel Sodium). ACTONEL is a biphosphonate, it is available in tabs 5, 30, 35, 75 and150 mg once a week dose packs. Dose as follows: 5mg/day, 35 mg/week, or 75 mg /day for 2 days once a month or 150 mg once a month. Actonel and other biphosphonates are indicated both for treatment or prevention of Osteoporosis in menopausal, postmenopausal females as well as Osteporosis in males. ACTONEL is also available as ACTONEL PLUS CALCIUM as a blister package containing 28-day course therapy per wee k as follows: #4 ACTONEL 35 mg tablets for the first day and # 24 Calcium Carbonate 1250 mg tablets for days 2 to 7h. Either kind of ACTONEL, for the first day dose has to be taken with Sounces of plain water, 30 minutes before the first meal or drink of the day. Another biphosphonate is BONIVA (Ibandronate). In general the biphosphonates act as inhibitors of osteoclasts-mediated bone resorption thus inducing osteoblast activity to favor bone mass. The recommended dose of BONIVA is 100-150 mgs once a month or 2.5 mg per day along with 400 IU of Vitamin D3 plus 500 mg of Calcium. Dose of 2.5 mg a day reduces the incidence of second bone fracture. Another biphosphonate is FOSAMAX ( Alendronate) available in tablets 5, 10, 35 and 70 mgs. It is also available as FOSAMAX PLUS VIT D3, strengths 7Omg/ 2800 IU and 7Omg/5600 IU tabs. The recommended dose is one tablet once a week or 10 mg tabs per day

CALCIUM ACETATE

Phospho-LO gel caps 667 mg. Mostly indicated in concomitant hyper phosphatemia in end-stage renal failure (dyalisis). Dose: 2 gel caps with each meal.

CALCIUM CITRATE (Active Ca). Usually mixed with Vitamin D3, Vitamin K, Mg 100 mg and calcium 200mg. Take 4 tabs/day with meals.

OTHER TREATMENTS: Calcitonin, Calcitriol and Genestein aglycone.

MIACALCIN (Calcitonin-Salmon) Calcitonin is a polypeptide hormone secreted by cells of the Thyroid gland. When provided reduces calcium in serum and reduces and reduces calcium bone resorption. It is used both in hypocalcaemia and postmenopausal osteoporosis. Dose for the latter 100 IU subcutaneous or IM every other day. Simultaneous give Calcium Carbonate 105 Gm and Vit D 400 IU per day. MIALCALCIN is also available as Nasal Spray, one spray (200 IU) per day. Monitor effectiveness of treatment with periodic lumbar vertebral bone density studies, also periodic analysis of serum Calcium, Magnesium and Alkaline Phosphatase levels, and also 24 hours urinary calcium and phosphates levels.

RECALTROL (Calcitriol) Occurs naturally in humans. It is the active form of Vitamin D3 (cholecalciferol).

FOSTEUM (Genestein Aglycone). It is given as a dietary management of metabolic process of Osteopenia and Osteoporosis. Genetein is obtained from soy, citrated zinc and cholecalciferol (Vit D3).

Mild hypocalcemia is usually asymptomatic. Moderate to severe hypocalcemia usually presents as: Tingling sensation, paresthesias, cramps, increased neuromuscular excitation, tetany, laringospasm, and even tonic-clonic seizures. If low calcium is concomitant to low PTH activity the symptoms may include: Total body hair loss (alopecia totalis) starting in infancy, grooved finger nails, cataracts, brain basal ganglia calcifications, mental depression, chronic anxiety, and delusions. Hypocalcemia may also be present in Vitamin D deficiency, poor nutrition, starvation, and mal absorption disorders. Some cases of chronic hypocalcemia in adults may follow thyroid gland surgery or radiation.

CALCIUM AND PHOSPHATE METABOLISM

Calcium and phosphate homeostasis is regulated by PTH and 1,25 dihydro Vitamin D (Calcitriol) through the effects of the kidneys, the intestines and the PTH gland. The l,25 dihydro Vitamin D is the only active Vitamin D. It is formed from the inert 25 OH vitamin D3, which is stored in fat tissue as a reserve.

VITAMIN D

Vitamin D is critical to preserve bones but it is also important to protect the body from certain diseases like cancer s of the Prostate, Breast and Colon, also other conditions like Non-Hodgeking Lymphoma, Rheumatoid Arthritis, Type II Diabetes, Macuiar Degeneration, Multiple Sclerosis (MS), Fib romyalgia, Gingivitis and others. It also promotes the efficiency of the immune system, regulates the cell growth, and has also anti inflammatory properties. There a re basically two kinds of Vita min D: From animal source, CALCIFEROL (Vitamin D3, and from plants source, ERGOCALCIFEROL (Vita min D2). Vitamin D is soluble in fat just as Vitamin A, Vitamin E, and Vitamin K are. The normal, recommended daily dose is 800-1000 international units (IU). The major natural sources of Vitamin D are fish, especially Salmon, Tuna, Sardines, Mackerel, and Cod Liver. The following are the people more at risk for Vitamin D deficiency: Older adults, people with limited sun exposure, the use of skin screen products, fair skin (less melanin), some mal absorption diseases such as Crohn’s , pancreatic deficiency, cystic fibrosis, sprue, liver diseases and post gastric by-pass surgery.

Complex Regional Pain Syndrome

Symptoms And Treatment of CRPS:

The current knowledge of the cause of CRPS is damage to:

  • The C and A delta nerve fibers.
  • The Somatic nerves.
  • The CNS pathways (as it happens in strokes and spinal cord injuries).
  • The C & A delta fibers reside in the dorsal roots and conduct the nociceptive pain, as they innervate mostly the soft tissues and bones. Those fibers seem to activate the afferent pathways, involved in:
  • The discriminatory  pain signals ,( location, intensity and quality).
  • The affective system (the unpleasant sensation of the stimulus).
  • The sympathetic (autonomic system).
  • The immune system.

SIGNS AND SYMPTOMS OF CPRS

According to the International Association of the Study of Pain (IASP)I, the signs and symptoms of CRPS are:

  • Abnormality of pain processing: (Allodynia, Hyperalgesia, hyperpathia).
  • Skin changes in color and temperature (bluish, reddish or paleness).
  • Neurogenic edema, due to vasomotor and sudomotor dysregulation.
  • A motor syndrome (weakness and eventually disuse muscle atrophy).

Patients with typical CRPS may present numerous other symptoms, such as:

  • Tremors
  • Spasms
  • Dystonia
  • Myoclonus
  • Parasomnias
  • Reduced concentration
  • Gastroparesis
  • Dysphagia
  • Hoarseness of voice

  Less Frequent:

  • Presyncopes Episodes
  • Rash
  • Pruritus
  • Headaches
  • Blurry Vision

CRPS incidence is 40/17000 for females and 11.9/100000 for males, and is more frequent in the ages of 37-64 years.  The more frequent causes of CRPS are bone fractures, muscle and ligament sprains, soft tissue trauma, surgery, etc. The set of symptoms vary, but is usually out of proportions (exaggerated) for the extension of initial injury. It does not follow a sensible anatomical distribution and may spread in characteristic pattern over time. The extraterritoriality of the pain may be due to diffuse wallerian degeneration.

The persistent pain may be maintained by:

  • Neuromas
  • Poorly healed fractures
  • Brachial plexus traction injuries of UE.
  • Chronic root irritation (radicuiitis)
  • Failure of inhibition at the dorsal horn level.

NEUROBILOGY OF CRPS

The nerve injury seems to activate the GLIAL cells (microgia, astrocytes and oligodendrocytes). For a long time glial cells consider to be just inactive, non neuronal cells of tissue support of the NS. The current knowledge is that the GLIAL cells become activated after nerve injury and once activated release proinflammatory CYTOKINES, such as:

  • Tumor Necrosis Factor (TNF)
  • Reactive Oxygen Species (ROS)
  • Nitrous Oxyde (NO)
  • Excitatory Amino acids (EAA)
  • Prostaglandins (PG)
  • Interleukin 1
  • Interleukin 6

Once such cytokines are released in the Dorsal and Ventral Horns of the spinal cord, are responsible for the development, spread and maintenance of neuropathic pain. Other important molecules of the inflammatory “soup” at the site of injury coming from the blood and, invade the immune cells, and include:

  • Proton
  • Serotonin
  • Bradykinin
  • Epinephrine
  • Lipoxoxygenases
  • Brain Derived Neurotropic Factor(BDVF) Adenosine
  • Neurotropins
  • Substance P and Calcitonin
  • Generated Peptides(CGRP)

DOES THE IMMUNE SYSTEM HAVE ANY ROLE IN CRPS?

The answer is YES. Both microglia and astrocytes are the primary immune component in the CNS and become activated by nerve and tissue damage or by inflammation and act in persistent pain states . The presence of proinflammatory cytokines can be measured in CSF along with Glutamates and Nitric Oxyde metabolites.

TREATMENT OF CRPS

At the time of this discussion, standard therapy for CRPS is limited. Early diagnosis is the most important, especially:

  • Traction injuries
  • Recurrent disc disease
  • Poorly healed fractures
  • Neuromas, etc.. Some of the earliest procedures are sympathetic blockades, while the patient has sympathetically maintained pain;
  • Many early CRPS cases are misdiagnosed and labeled as fibromyalgias when symptoms may arise from brachia| and cervical plexitis, frequently common in automobile accidents.
  • The use of Opiod pain medications is not usually effective, but if any has to be used, Methadone at low doses is the most adequate.
  • GABA agonists are good in certain cases, such as Pregabalin, Cymbalta and amitriptyline.
  • One of the newest medicines being tried is KETAMINE.
  • It is necessary to do a basic EKG and if possible a 2-D echocardiogram, and a neuropsychological evaluation.
  • The protocol is to use 10 sessions of 4 hours IV infusion of 200 milligrams of Ketamine as an outpatient; monitoring the BP, Pulse and EKG monitoring. Give Valium or Versedl, plus Clo nidine. At the end of the session give 2 mgs of Ativan, po.
  • Result is about 80% of patients obtain 6080 %  pain relief that may last for two to three months.
  • Give a buster at one month and at 3 months
  • Other approaches in the near future are: Lidocaine infussiions, Propentofylline, a phosphodiesterase inhibitor that can block the activation of  microglia. Other alternative to be tried is Thalidomide and Chyoneurolysis of neuromas that now is able to be seen under MRI or ultrasound.