WHY PROLONG USE OF PROTON PUMP INHIBITORS CAUSE OSTEOPOROTIC FRACTURES

WHAT IS PROTON PUMP INHIBITORS?                                                                      Proton pump Inhibitors are highly potent and effective gastric acid secretion Inhibitors. They are sold as over the counter medication and widely used worldwide to treat acid related problems.

INDICATION OF PROTON PUMP INHIBITORS (PPIs)
• Peptic ulcers
• Eradication of H-pylori infection
• For prevention of gastroduodenal ulcer secondary to use of non steroidal anti inflammatory drug (NSAID).
• Zollinger Ellison syndrome
• Gastroesophageal Reflux(GERD)
HOW PPIs SHOW SUPERIOR EFFICACY OVER THE OTHER DRUGS AVAILABLE TO TREAT ACID RELATED DISEASES?
Proton pump Inhibitors are very site specific drugs which blocks final path of acid secretion in stomach by irreversible binding to hydrogen-potassium ATPase enzymes which resides on the luminal membrane of parietal cells. Irreversible binding to site specific not only make it a potent drug for acid related problems but also decreases its frequency of administration and increase patients compliance. proton pump Inhibitors includes omeprazole, lansoprazole, dexlansoprazole, esomeprazole, rabeprazole and pantoprazole.

WHAT WILL BE THE CONSEQUENCES OF CHRONIC OR HIGH DOSE USE OF PROTON PUMP INHIBITORS?
Proton pump inhibitors are considered to be safe for more than 3 decades which have low incidence of side effects and have superior efficacy for acid related disorders. The frequent use of PPIs and long term maintenance for prolong period of time raise the question about its consequences. Many people in hospital setting initiates proton pump Inhibitors during treatment but afterwards people continue to use it without any medical guidance because it is an OTC drug. Generally OTC PPIs are prescribed in low doses for up to 14 days of treatment which is not more than 3 times per year in contrast to prescription PPIs. The long term use of PPIs increases many risk factors. The consequences secondary to PPIs used can be classify as follow,

1. MICRONUTRIENT DEFICIENCY
Malabsorption of calcium, magnesium, vitamin B12 and iron is supposed to be occur secondary to long term use of proton pump Inhibitors.

2. INFECTION
Clostridium difficile and pneumonia are infectious related risks of long term use of PPIs because stomach secretes acidic fluid as low as PH 2 which also sterilized ingested food bacteria. Hypo acidity cause the changes in the normal flora of gut and increase risk of infections.

3. Dementia
Increase risk of dementia is also supposed to be adverse effect of chronic use of PPIs. The reason may be increase amyloid protein synthesis and decrease in it degradation process

4. LOSS OF MINERALS
Loss of minerals are supposed to be associated with bone fracture, osteoporosis and decrease bone mineral density after chronic use of PPIs.

5. GASTRIC CANCER
Decrease acid secretion increase serum gastrin and Enterochromaffin cells production. Persistent hypergastrinemia and Enterochromaffin cells hyperplasia and bacterial over growth are the potential factors for developing gastric cancer after using PPIs for prolong period of time.

6. CHRONIC KIDNEY DISEASE (CKD)
CKD is supposed to be cause by acute intersttial nephritis which with the passage of time progress into nephron injury after chronic use of PPIs.

7. ACID REBOUND
Abrupt discontinuation of PPIs cause acid rebound. This may be due to persistent hypergastrinemia.

8. CARDIAC ABNORMALITIES AND SUDDEN DEATH
Mostly cardiac patients use PPIS. Loss of minerals cause CVS changes and may cause sudden death.

HOW PPIs CAUSE OSTEOPOROSIS RELATED FRACTURE?
The following factors may be related with PPIs associated OSTEOPOROTIC FRACTURE mainly of spine, hips and wrist.

• FRACTIONAL CALCIUM ABSORPTION
The strength of relation between osteoporotic fracture and interference with calcium absorption with strong inhibition of gastric acidity is weak. This association becomes significant when PPIs use is in higher daily doses or when the use of PPIs is chronic or contineous one. Limited animal and human ortho studies shows that for insoluble calcium salts like calcium carbonate acid is required which dissolve and ionizes soluble calcium and allow the absorption of ca++ ions. Due to pharmacological action of PPIs, there is hypochlorhydria which may reduce calcium absorption. As we all know very well that bone is like a calcium bank and may contain greater than 99% of a body calcium. Due the negative calcium balance in blood, there will be increase osteoclastic activity in bone that is resorption or break down of bone to maintain blood calcium level. This break down of bone or bone mineral loss make the bone fragile and increases the risk of osteoporosis related fracture. However, this hypothesis is not strong because calcium from calcium citrate salt is not dependent on acid PH for absorption and absorption of calcium from diet is also not affected by hypochlorhydria secondary to long term PPIs used.

WHICH CALCIUM SALT SUPPLEMENT (calcium citrate salt or calcium carbonate) SHOULD BE PREFER FOR PPIs USERS?
No clinical evidence till now showed supremacy of one salt over another one in preventing osteoporotic fracture secondary to PPIs used.

• However, through calcium citrate salt absorption of calcium is regardless of acid or PH as compare to calcium carbonate which require acid for calcium absorption. Therefore, calcium citrate may be recommended as calcium supplements in PPIs users.
• Another counseling is that if calcium carbonate is given with meal especially with breakfast then calcium absorption problem from carbonate salt secondary to hypochlorhydria is minimized.
• The bioavailability of calcium from the natural products like milk or cheese is not acid dependent.

• HYPERGASTRINEMIA
Potent inhibition of gastric acid secretion increases serum gastrin level which in turn induce secondary hyperparathyroidism that could change the bone metabolism by worsening bone mineral loss.

• INHIBITION OF OSTEOCLASTIC PROTEIN TRANSPORT SYSTEM                  Limited in vitro and human data suggest that long term PPIs use of omeprazole may decreases bone resorption through the inhibition of osteoclastic protein transport system (osteoclastic vacuolar hydrogen-potassium ATPases) which increases osteoporosis by decreasing calcium absorption.

• NON TRAUMATIC TUMOR
Long term use of PPIs is related to occurrence of non traumatic tumor which might increases risk of hip fracture.

• HYPOMAGNESEMIA
Long term use of PPIs decreases magnesium absorption through intestine. Hypomagnesemia decreases muscles function, cause seizures and tetany, arrhythmia and osteoporosis.

How HYPOMAGNESEMIA cause osteoporosis?
The following means are responsible for osteoporosis secondary to hypomagnesemia.
• Magnesium has effects on osteoblast and osteoclast cells of bone. Deficiency of magnesium altered size and structure of bone crystals.
• Deficiency of magnesium reduces concentration of PTH hormone and active form of vitamin D and both hormones are important for bone health.
• Deficiency of magnesium affects bone remodeling by increasing inflammatory proteins cytokines.
• Deficiency of magnesium cause low grade acidosis and cause calcium loss from bone and affects bone mineralization.
• Deficiency of magnesium affects blood flow to bones through endothelial dysfunction.

• IMPAIRED ABSORPTION OF VITAMIN B12
Potent acid suppression cause vitamin B12 malabsorption which interfere with the homocysteine level which ultimately affects collagen (an initial substance for bone formation) cross linking and ultimately affects tendon.

FDA WARNING FOR CHRONIC PPIS USED
In 2010, FDA issued a warning about the relation between chronic use of PPIs and increased risk of osteoporotic fracture that is fracture of spine, hips and wrist.

CONCLUSION
Increase risk of Osteoporotic fracture especially hips fracture secondary to use of PPIs is higher among patients taking long term high doses (higher than OTC PPIs doses) or among those patients whose doses progressively increases with treatment duration (one year or more ). Hip fracture is very common in senile osteoporosis (a type of osteoporosis progress with aging). Physicians should be judicious for the prescription of PPIs and for long term use there should be strong validated indication. Patients who are at risk of developing fracture especially older patients and long term PPIs user should be monitored with intense care. On the basis of recent evidence, to avoid bone fracture PPIs discontinuation is not recommended. The purpose of this article is to discourage self medication with out medical guidance and inadequate prescriptions. For valid indication minimum effective doses for shortest period of time should be sort out. Long term use of PPIs should be sought unless and until there is strong, recognize and valid indication. Although the relation between long term use of PPIs adverse effects and their clinical impact on body is still require validation and research.