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Other Mechanisms Inducing Hypocalcemia

Calcium Complexation: Many agents can induce hypocalcemia by causing complexes to form between the medication and serum calcium.This complexation of calcium is so rapid and massive that maximal PTH secretion is inadequate to compensate for the sudden drop in serum calcium. A classic example of this phenomenon is foscarnet, an antiviral agent often used in immunocompromised patients. Foscarnet chelates with calcium, resulting in a reduction in both total and ionized calcium serum levels. Ethylene glycol has also been identified with this complexation phenomenon.

Altered Gastric Acidity: Medications that alter gastric acidity may also impact the absorption of calcium from the diet. Drugs that increase gastric pH can also decrease the breakdown of fat necessary to complex with calcium, thus reducing gut absorption.H₂-antagonists such as cimetidine have been implicated in this phenomenon. While not yet reported in the literature, other agents known to increase gastric pH can also inhibit gastric absorption of calcium salts through similar mechanisms. Such agents include the proton pump inhibitors omeprazole and lansoprazole.

In addition to its presence in antacid preparations, aluminum is found as a contaminant in several of the additives in total parenteral nutrition (TPN) solutions. Originally linked with protein hydralysates, total parenteral nutrition-induced metabolic bone disease still occurs in patients receiving chronic TPN. It is thought that calcium gluconate and potassium phosphate salts contain sufficient aluminum to impair bone formation or mineralization. Therefore, it has been suggested that the use of calcium acetate salts and sodium phosphate salts may reduce these risks.

Osteoporosis Drugs: Agents typically used to treat osteoporosis can themselves induce metabolic bone disease if used too aggressively. Calcitonin and bisphosphonates can cause chelation and end organ inhibition, resulting in an overall reduction in osteoclast bone resorption.Sodium fluoride, an agent often used to treat drug-induced osteoporosis, can also cause hypocalcemia by inducing excessive rates of skeletal mineralization. This can create calcium-chloride complexes.

Osteomalacia may also result from a deficiency or impaired utilization and/or excretion of inorganic phosphate. The result is hypophosphatemia. Patients with peptic ulcer disease who chronically use aluminum-containing antacids may be at risk of developing hypophosphatemia. This is due to complexation of the aluminum with the ionorganic phosphates residing in the intestine. As a result, an insoluable salt is formed.

Blood Transfusions/plasmapheresis: Other therapies — such as blood transfusions or plasmapheresis — may predispose patients to hypocalcemia due to the presence of the anti-clotting agents in the blood products. For example, calcium citrate salts present in blood products can induce hypocalcemia by chelating with serum calcium. Similarly, patients undergoing radiologic procedures with contrast dyes containing EDTA (ethylene diamine tetracetic acid) may also have an increased propensity to develop hypocalcemia as a result of chelation of calcium with EDTA. Fortunately, however, the resulting hypocalcemia in these cases appears to be mild.

Lifestyle Choices That Induce Bone Loss

Excessive alcohol use and smoking have been associated with osteoporosis.

Smoking: Tobacco smoking appears to have an antiestrogen effect. Estrogen prevents bone breakdown through several possible mechanisms, including blocking bone resorption by shortening the lifespan of osteoclasts. Osteoclasts are responsible for bone breakdown. In addition to undergoing the pharmacologic effects of tobacco, smokers tend to be less physically active and more prone to poor nutrition, thus increasing their risk for osteoporosis.Smokers should be encouraged to quit so as to reduce further tobacco-related bone loss.

Excessive Alcohol: Alcohol abuse is a risk factor for osteoporosis. Originally, malnutrition and liver disease, often associated with chronic alcohol abuse, were thought to predispose patients to osteoporosis. However, more recent research has shown that alcohol-associated bone disease is multifactorial. Hypocalcemia results from the transitory hypoparathyroidism seen with acute alcohol toxicity. Ethanol itself has been shown to inhibit osteoblast formation, thus decreasing the rate of bone formation. Ethanol also appears to induce the cytochrome P-450 system, which increases the rate of vitamin D metabolism. Ethanol also inhibits the renal and hepatic hydroxylation of vitamin D, further decreasing activation of already low levels of vitamin D.

Conclusion

Osteoporosis and related bone disorders easily come to mind when one pictures an elderly, postmenopausal female. However, it is important for pharmacists and other healthcare providers to recognize the potential for bone damage in a wider patient population, due to drug therapy. A number of drugs have been documented to directly interfere with the absorption and/or activities of calcium or vitamin D — agents critical to the proper maintenance of healthy bone. Other drugs may have a more indirect action on bone structure, such as agents that reduce magnesium stores. The net effect of lowered magnesium levels is reduced serum calcium levels, to the detriment of healthy bone. Pharmacists should be familiar with drugs that can alter calcium or vitamin D levels in patients. Patients at risk for bone disorders due to medications should be counseled about this risk and advised of steps they can take to prevent or minimize bone damage.

Glucocorticoid Therapy and Bone Loss

Patients receiving long-term glucocorticoid therapy for conditions such as inflammatory bowel disease and rheumatoid arthritis are also at risk of developing drug-induced bone loss. This effect appears to depend on dose and duration of therapy. Most bone loss has been documented to occur during initiation of treatment, with eventual plateaus achieved within 6 months to 1 year of therapy. Atraumatic fractures involving the vertebrae and ribs are seen in 30% to 50% of patients receiving chronic steroid therapy.

There are several mechanisms associated with glucocorticoid-induced bone loss. Steroids decrease bone remodeling by inhibiting osteoblast maturation and subsequent bone formation. Glucocorticoid use causes a net negative calcium balance and increased bone resorption due to suppressed intestinal absorption of calcium in conjunction with increased renal calcium and phosphate excretion and subsequent decrease in renal tubular calcium resorption.

Even the frequent use of inhaled steroids has been associated with induced bone loss and a decrease in bone density. These findings have been confirmed in a recent study conducted in 209 premenopausal asthmatic women who frequently inhaled steroids. The subjects were divided into three subgroups — two that used inhaled steroids at different dosages and a control group that did not use steroids. Bone density was assessed over a three-year period. The two subgroups using inhaled steroids showed decreases in bone density, with greater bone loss associated with higher steroid doses.

The authors concluded that, while inhaled steroid use should not be discouraged in this patient population, careful attention should be given to ensure that patients receive adequate amounts of calcium and vitamin D. In addition, bone mineral density should be measured every six months so that alternative therapies and interventions can be considered before excessive bone loss occurs. Although this study involved females, the authors suggest that similar results could be expected in males receiving similar doses of inhaled steroids.

Anticoagulants and Bone Loss

Heparin Use: The development of osteoporosis has long been associated with chronic heparin therapy. The mechanism for heparin-induced osteoporosis has not yet been established, although several theories have been postulated. Some theories include abnormalities in vitamin D metabolism, enhanced osteoclast activity and diminished osteoblast activity. Patient complaints of back pain, in addition to vertebral compression fractures and a decrease in bone mineral density, have been documented. The severity of osteoporosis has been associated with the duration as well as the daily dose of heparin. Research by Rupp, et al. and Griffith, et al. places patients receiving doses greater than 30,000 units per day for more than three months at greater risk. Treatment typically involves discontinuation of heparin. Both unfractionated and the new low molecular weight (LMW) heparin products have been implicated, although animal studies suggests a lower incidence of osteoporosis with LMW heparin.

Warfarin Use: Heparin is the not the only anticoagulant associated with bone disease. Chronic therapy with warfarin has been associated with bone loss via a reduction in carboxylated fragments of osteocalcin — the major noncollagenous protein contained in bone. The normal metabolism of vitamin K involves gamma carboxylation of osteocalcin, which maintains bone growth. Knaper and colleagues noted a reduction in bone turnover among postmenopausal women receiving supplemental vitamin K. This contradicted research by Rosen, et al., who reported no difference in skeletal integrity in adults receiving long-term warfarin versus controls.Additional research is warranted to determine the significance of warfarin-associated bone loss.

Thyroxine and Bone Loss
Excessive therapy with thyroxine has also been associated with bone loss. Thyroid supplements are one of the most frequently prescribed medications; more than 10% of postmenopausal women receive thyroid hormone replacement. Euthyroid patients receiving suppressive thyroxine therapy are also at risk.As with other cases of drug-induced bone disease, dose and duration of therapy are implicated.Exogenous hyperthyroidism-induced bone loss is due to increased bone resorption, subsequent decreases in PTH, and increases in ionized calcium. Maintaining thyroid hormone replacement at physiologic doses appears effective in minimizing bone loss due to therapy.

Agents That Impair Absorption of Calcium

Medications that impair the absorption of calcium can have a negative impact on serum calcium levels. The malabsorption of calcium has been documented in patients receiving colchicine, mineral oil, or sodium sulfonated polystyrene resin. Similarly, agents known to enhance the renal excretion of calcium — such as loop diuretics — also predispose patients to hypocalcemia.

Magnesium Depletion: In addition to medications that directly alter serum calcium levels, agents that deplete the body of magnesium ultimately cause hypocalcemia. In fact, drug-induced hypocalcemia is often due to a depletion of magnesium stores. Magnesium deficiency can induce a transient hypoparathyroidism by reducing the secretion of parathyroid hormone (PTH) and a blunted PTH response. This result is an inhibition of the hypocalcemic feedback loop. Other agents that suppress PTH secretion — with resulting inhibition of the hypocalcemic feedback loop — include aluminum salts and excessive alcohol.

Cisplatin, Aminoglycosides, Cyclosporine: Cisplatin, aminoglycosides, and cyclosporine are known to increase magnesium wasting through a variety of mechanisms. Cisplatin-induced hypomagnesemia is dependent on dose and duration of therapy. Cisplatin induces hypomagnesemia by causing direct injury to the mechanisms of magnesium reabsorption in the ascending limb of the loop of Henle and the distal tubule. Forastiere and colleagues reported that the total exposure of free platinum contributes to direct injury and renal toxicity. Mavichak, et al. have also suggested that cisplatin causes lesions in the distal renal tubules responsible for renal magnesium losses. Carboplatin, an antineoplastic agent with a chemical structure similar to cisplatin, has been reported to have a lower incidence of hypomagnesemia.

Renal wasting of magnesium is also fairly common in patients receiving prolonged, high doses of aminoglycosides. Aminoglycosides can inhibit the proximal tubular transport of magnesium in the kidney, predisposing patients with poor magnesium intake to lower magnesium levels. Transplant patients receiving cyclosporine also may experience severe hypomagnesemia due to increased urinary excretion of magnesium.Table 2 lists agents known induce hypocalcemia by depleting magnesium stores. Treatment for hypocalcemia induced by hypomagnesemia involves correcting hypomagnesemia first, then managing serum calcium levels.

Agents That Impair Absorption of Vitamin D

Older Anticonvulsants: Older anticonvulsants, such as carbamazepine, phenobarbital and phenytoin, have been associated with drug-induced osteomalcia.It has been postulated that these agents increase the degradation of 25(OH)D₃, the predominant circulating metabolite. However, many early studies were confounded because they were conducted on institutionalized patients who were predisposed to other risk factors, such as poor dietary vitamin D intake and/or reduced exposure to sunlight. Tolman and colleagues reported a positive correlation between the incidence of osteomalacia and the duration of anticonvulsant therapy; they documented the development of bone disease in over 75% of patients receiving anticonvulsant therapy for periods greater than 10 years. Hahn, et al. also reported that phenytoin reduced calcium absorption by directly inhibiting intestinal transport.

Chronic Laxative Use: Laxative abuse has also been implicated in compromised bone status. The overuse of cathartics has been associated with malabsorption of vitamin D and calcium. Use of irritant laxatives such as phenolphthalein and bisacodyl may damage the structural integrity of the intestinal mucosa and cause impaired colonic reabsorption, steatorrhea, and malabsorption of vitamin D and calcium. Orally ingested mineral oil can coat ingested food particles along with the surface of the intestines. It forms a mechanical barrier to the digestion and absorption of nutrients. Mineral oil also increases gastric motility, which reduces the time required to adequately absorb ingested nutrients. Moreover, studies have shown that mineral oil — especially if taken at mealtime or during the postprandial absorptive period, when nutrients are absorbed — can prevent the absorption of vitamin D.

Other Agents: Other agents that impair the absorption of vitamin D and have shown documented increased risk of deficiency include the absorbable and nonabsorbable types of hypo-lipidemic drugs. Similarly, cholestyramine, an anion-exchange resin, has been found to bind bile salts and interfere with the bioavailability of numerous fat-soluble nutrients, including vitamin D. Knodel and colleagues associated large doses of cholestyramine (>32 g/day) with the malabsorption of fat-soluble vitamins. They also observed cholestyramine-induced osteomalacia resulting from impaired absorption of vitamin D.

Agents That Cause Secondary Impairment of Vitamin D

Isoniazid/cimetidine: Medications that inhibit the hepatic and/or renal hydroxylation of vitamin D subject patients to increased development of bone disease due to the secondary impairment of calcium absorption. For example, drugs such as isoniazid and cimetidine inhibit the hepatic and renal hydroxylation of vitamin D. This results in a functional vitamin D deficiency — with a secondary impairment of calcium absorption. Odes, et al. concluded that even short-term therapy with cimetidine altered vitamin D metabolism in humans. The researchers concluded this after monitoring levels of 25(OH)D₃ for 30 days in patients receiving treatment. Calcium channel blockers such as verapamil can also have a negative impact on vitamin D levels by decreasing its hydroxylation in the body.In addition, medications that promote the catabolism of vitamin D metabolites, such as phenytoin and phenobarbital, have the same effects.

One of the most prevalent of the degenerative diseases in the United States today, osteoporosis affects over 10 million individuals. An additional 18 million are at risk of osteoporosis due to low bone density. The majority of patients affected are postmenopausal females. The number of cases of osteoporosis is expected to rise substantially in the next several decades, as life expectancy increases and the world population expands. This growing elderly population inevitably will be affected by multiple pathological processes that require drug therapy. Unfortunately, some medications may cause hypocalcemia and accelerate bone loss. Patients who experience these effects can present with osteoporosis, osteopenia, and/or osteomalacia.

Osteoporosis, Osteopenia, Osteomalacia

Defined as a reduction in bone mineral mass and an increase in the porosity of remaining bone cortices and trabeculae, osteoporosis is associated with bone thinning. In addition, there is a resultant decrease in bone strength and increased susceptibility to skeletal fracture — even with minimal trauma. Osteopenia is the loss of bone density, as seen on radiographic exam. The reduced density may occur in all bones or be limited to a specific bone, as in the case of disuse atrophy. Osteomalacia and rickets are disorders that involve the softening of bone due to a failure of osteoid matrix cells to mineralize properly. This failure to mineralize occurs as a result of vitamin D deficiency and inadequate intestinal absorption of calcium and phosphorus.

While none of the above disorders is involved in development of bone disease, all are associated with an alteration in normal bone development. Although in osteoporosis there is typically a net excess of bone resorption in relation to bone formation, the exact amount may vary from patient to patient. Numerous factors may increase the risk of developing bone disease, including the use of certain medications. Table 1 provides a list of medications associated with inducing bone disease.

Agents Needed for Bone Maintenance

The primary agents responsible for bone remodeling and mineral metabolism are parathyroid hormone (PTH), vitamin D, and calcitonin.

Role of PTH: Parathyroid hormone stimulates bone resorption by stimulating increased reabsorption of calcium and decreased phosphorus reabsorption in the kidney. PTH also increases the renal production of 1,25-dihydroxy D₃ (calcitriol), thus increasing the intestinal absorption of calcium and phosphorus. This ultimately leads to bone mineralization and resorption. The outcome is a net increase in ionized serum calcium levels.

Role of Vitamin D: Vitamin D is necessary for proper bone maintenance. It can be ingested from dietary sources such as fatty fish or from fortified foods such as milk, bread products, cereals and margarine. Alternatively, it can be synthesized endogenously in the skin during sun exposure. Regardless of its source of origin, vitamin D must be hydroxylated in the liver to its major circulating form — 25(OH)D₃. Twenty-five (OH)D₃ is biologically inert on calcium metabolism at physiological concentrations; it requires further hydroxylation in the kidney to its biologically active metabolite, 1,25(OH)₂D₃ (calcitriol).

The active form of vitamin D primarily maintains serum calcium levels within normal range. It accomplishes this by enhancing the efficiency of intestinal calcium absorption and/or mobilizing calcium stores from bone. Any medication that interferes with the metabolic conversion of vitamin D to its active form will impair calcium absorption and alter bone status. For example, even the topical application of sunscreen products containing para-amino benzoic acid (PABA), with a protection factor of 8, can almost completely eliminate the in vivo cutaneous synthesis of vitamin D and predispose chronic users to osteoporosis.Table 2 provides a list of medications and respective mechanisms involved in precipitating bone disease.

Calcium plus estrogen leads to stronger bones.

By consuming large amounts of calcium, women who are taking estrogen replacement therapy will have denser, stronger bones than women on HRT alone, concludes an analysis of 31 earlier studies. By adding calcium to the diet, the benefits of HRT were doubled. Calcium consumption averaged 1,183 mg per day in women who took supplements, compared to consumption of 563 mg per day in women who did not take supplements. Calcium may have a synergistic effect on estrogen and it also may be more effective than estrogen alone in increasing bone mass in the hip and forearm where estrogen is less effective.