Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Consensus

Effect and Mechanism of Action

Gentamicin exhibits a significant risk of nephrotoxic effects and can cause increased urinary calcium loss. Concomitant administration of calcium may have a protective effect but may also potentiate gentamicin-induced nephrotoxicity. Neurotoxic effects are also well known.

Neomycin impairs calcium absorption when taken orally.

Research

Animal studies indicate that renal tubular damage caused by aminoglycosides, such as gentamicin, can lead to hypocalcemia combined with hypokalemia, hypomagnesemia, and alkalosis. ^42-44 In a retrospective study, Schneider et al. ⁴⁵ found that coronary artery bypass graft (CABG) patients who received both a bypass prime with a high calcium concentration (6.25 mmol/L) and gentamicin perioperatively had a higher incidence of renal failure compared with those who received only the prime, gentamicin alone, or neither.

Reports

A 12-year-old boy developed renal wasting of magnesium, calcium, and potassium, with secondary hypomagnesemia, hypocalcemia, and hypokalemia (without hyperaldosteronism), after treatment with 14,400 mg gentamicin over 4 months. ⁴⁶ Other case reports involving gentamicin have described similar adverse effects on electrolytes, particularly hypomagnesemia. ^47-49

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians administering extended courses of gentamicin or other aminoglycosides should monitor kidney function as well as plasma magnesium, calcium, and potassium levels during and after treatment. Magnesium levels in red blood cells (RBCs) can provide a more reliable picture of magnesium status than testing serum magnesium. Serum creatinine, blood urea nitrogen (BUN), and creatinine clearance should also be measured before initiating therapy and monitored throughout treatment. Nutritional support may be required to restore normal levels of calcium and other important minerals. Prolonged courses of gentamicin should be avoided if less nephrotoxic antibiotics are suitable. Oral neomycin in preparation for surgery is unlikely to produce clinically significant deficiencies.

Calcium coadministration in the range of 500 to 1000 mg per day may beneficial for individuals being treated with aminoglycosides for longer than 2 to 3 days. Slow-K and Micro-K are typical examples of the potassium suggested by most physicians. Patients can further enhance their potassium levels by eating several pieces of fresh fruit each day. However, increasing potassium intake by any means is usually contraindicated and often dangerous in patients with reduced kidney function. Coadministration of magnesium in the dosage range of 300 to 500 mg per day is usually appropriate but should be done in collaboration with a physician trained and experienced in nutritional therapies. Magnesium supplementation is risky in patients with renal insufficiency and is usually contraindicated in such cases. It is also important to note that magnesium is needed to maintain intracellular potassium due to magnesium dependence of the membrane Na ⁺ , K ⁺ -ATPase enzyme, as well as calcium, because parathyroid hormone (PTH) is a magnesium-requiring hormone. Intravenous (IV) magnesium replacement is preferred for correction of frank hypomagnesemia.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect

Consensus

Effect and Mechanism of Action

The ability of amphotericin B to increase intracellular calcium concentrations is associated with the toxicity of this antifungal agent. Calcium depletion is a generally accepted adverse effect of amphotericin B; sodium, potassium, and magnesium are similarly depleted. Hyperphosphatemia has also been observed. This medication exerts adverse effects on renal function, but details of possible metabolic pathways are not known.

Reports

Amphotericin B lipid complex (ABLC) is a liposomal formulation that is less nephrotoxic than conventional amphotericin B and can be given more safely to patients with preexisting renal impairment with no apparent loss of efficacy. Nevertheless, cases of severe hyperphosphatemia resulting from high-dose liposomal amphotericin have been reported. ⁵⁰

Nutritional Therapeutics, Clinical Concerns and Adaptations

Physicians administering amphotericin B are advised to monitor electrolyte status and consider supplementation with a multimineral formulation during extended treatment. Aberrations of serum electrolytes, including calcium, concomitant with amphotericin therapy may require parenteral management.

	Potentially Harmful or Serious Adverse Interaction—Avoid
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Consensus

Effect and Mechanism of Action

Aluminum-based antacids may reduce calcium absorption and can complex with phosphates to cause a depletion of calcium stores. Aluminum hydroxide causes increased loss of calcium through urine and stool.

Calcium citrate has been found to act similar to citrus juice in significantly increasing aluminum absorption from antacids.

Research

Concomitant intake of calcium citrate can significantly increase aluminum absorption from both dietary sources and aluminum-containing antacids. ^51-54 Weberg et al. ⁵⁵ examined the mineral-metabolic effects of a 4-week course of a conventional low-dose aluminum-magnesium antacid in 10 healthy volunteers, who were given one antacid tablet after the three main meals and at bedtime (buffering capacity, 120 mmol/day). They observed significant changes from premedication state, including an increase in urinary excretion of magnesium, calcium, and aluminum; decrease in urinary excretion of phosphate; increase in maximal renal phosphate reabsorption; and increase in serum concentration of aluminum. All these parameters returned to normal levels within 3 to 4 days after cessation of antacids. ⁵⁵ In a study involving eight male subjects, Coburn et al. ⁵⁶ found that coadministration of 5 mL of aluminum hydroxide gel (2.4 g four times daily) and calcium citrate (950 mg four times daily) for 3 days “markedly enhances aluminum absorption from aluminum hydroxide” and increases urinary aluminum excretion. In a trial involving 30 healthy women, Nolan et al. ²⁵ observed that calcium citrate (800 mg elemental calcium daily) significantly increased absorption of aluminum from dietary sources (i.e., with no additional exposure to aluminum in antacids) and resulted in significantly increased urinary aluminum excretion and plasma aluminum level. During monitoring, however, they noted no changes in urine or whole-blood lead levels. Further research is warranted to determine whether long-term use of calcium citrate contributes significantly to aluminum accumulation and toxicity and the relative role of antacids in such risk.

Antacids containing magnesium and aluminum can increase calcium elimination, particularly urinary and stool loss. ⁵⁷

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing antacids containing aluminum (and magnesium) should advise patients to avoid calcium supplements, particularly calcium citrate, during the course of treatment; citrus juice is also contraindicated. In general, use of aluminum-based antacids should be discouraged given the mineral's inherent toxicity. The risks of an adverse reaction between calcium citrate and aluminum-containing compounds are especially high for individuals with kidney failure, particularly those on dialysis. Consider alternative approaches to antacid therapy using calcium or magnesium compounds without aluminum content.

Effect and Mechanism of Action

Many anticonvulsants, including phenobarbital, cause reduced calcium absorption with long-term use. ⁵⁸ Some anticonvulsants, such as phenytoin and phenobarbital, adversely affect calcium metabolism by reducing serum levels of calcidiol and thereby altering hepatic metabolism of vitamin D, at least in part by accelerating its metabolism and increasing the excretion of its metabolites. ^59,60 Thus, hypocalcemia and subsequent bone loss during anticonvulsant therapy may be the result of vitamin D deficiency. Consequently, by multiple possible mechanisms, anticonvulsant medications may reduce serum calcium levels.

Research

Long-term therapy with phenytoin and other anticonvulsants can disturb vitamin D and calcium metabolism and result in osteomalacia. Both epilepsy and anticonvulsant medications are independent risk factors for low bone density, regardless of vitamin D levels. Long-term anticonvulsant treatment can cause excessive metabolism and deficiency of vitamin D and is believed to be associated with decreased bone mineral density (BMD) and bone loss.

In vitro research involving rat bone culture by Somerman et al. ⁶¹ found that phenytoin reduced 1,25-dihydroxycholecalciferol and inhibited vitamin D–mediated bone resorption even after phenytoin treatment was discontinued. Several studies have found that patients on long-term anticonvulsant therapy exhibit reduced serum concentrations of 25-hydroxycholecalciferol. ^62,63 Both forms of vitamin D are necessary for calcium absorption. ^6,64

In a 1982 study involving 30 adult epileptic patients, Zerwekh et al. ⁶⁵ reported decreased serum 24,25-dihydroxyvitamin D concentration during long-term anticonvulsant therapy (with phenytoin, phenobarbital, or carbamazepine), with phenobarbital-treated patients exhibiting a significant decrease in serum 25-OHD. They noted that various anticonvulsant agents appear to exert different effects on vitamin D metabolism.

After finding no pattern of low serum levels of vitamin D (25-OHD) or radiological evidence of osteomalacia or rickets in more than 400 individuals using anticonvulsants in Florida, Williams et al. ⁶⁶ concluded that the climate provided adequate exposure to sunshine and thereby prevented the development of anticonvulsant-induced osteomalacia or rickets. “In contrast to reports from northern climates, we found minimal evidence of anticonvulsant-induced bone disease.” Subsequently, in a controlled trial, Riancho et al. ⁶⁷ studied 17 ambulatory epileptic children taking anticonvulsants for two seasons with high and low levels of solar radiation and observed that although serum 25-OHD concentrations were normal among medicated subjects during the summer, their levels were significantly lower than those of controls during the winter months.

In initiating a prospective 3-year study, Hunt et al. ⁶⁸ found that of 144 children and young adults who required anticonvulsant therapy, 52 were found to have serum alkaline phosphatase (ALP) levels elevated more than two standard deviations (SDs) above normal, and half these showed signs of rickets or osteomalacia. After slow and gradual but varying rates of response to calcitriol, all patients showed significant lowering of serum ALP levels by 30 months of follow-up. In a later controlled study, Jekovec-Vrhovsek et al. ⁶⁹ determined that bone strength improved (specifically, BMD increased) in 13 institutionalized children undergoing long-term anticonvulsant therapy who were supplemented for 9 months with 0.25 µg daily 1,25-dihydroxycholecalciferol vitamin D, the activated form of vitamin D, and 500 mg daily calcium.

Telci et al. ⁷⁰ compared bone turnover in 52 epileptic patients receiving chronic anticonvulsant therapy with 39 healthy volunteers as matched controls and found that the resorption phase of bone turnover is affected during chronic anticonvulsant therapy. Total serum ALP levels (a marker of bone formation) were significantly increased in patients from both genders compared with those of their controls. Among male epileptic patients, urinary deoxypyridinoline levels (a marker of bone resorption) were significantly increased while 25-OHD levels were significantly reduced compared with those of their controls.

Farhat et al. ⁷¹ compared the effects of various antiepileptic drugs (AEDs) on bone density in 71 adults and children anticonvulsant therapy for at least 6 months. More than half the adults and children/adolescents had low serum 25-OHD levels. Although this finding did not correlate with their BMD, the AEDs were strongly associated with decreased BMD in the adults, particularly at skeletal sites enriched in cortical bone. Furthermore, lower BMD was more consistently associated with enzyme-inducing agents (e.g., phenytoin, phenobarbital, carbamazepine, primidone) than with medications that did not induce enzymes (e.g., valproic acid, lamotrigine, clonazepam, gabapentin, topamirate, ethosuximide). These researchers concluded: “Generalised seizures, duration of epilepsy, and polypharmacy were significant determinants of bone mineral density.”

In 2001, Valmadrid et al. ⁷² published a survey of practice patterns of neurologists. They found that only 41% of pediatric and 28% of adult neurologists performed routine evaluation of patients receiving AEDs for either bone or mineral disease. Further, among those physicians who detected bone disease through such diagnostic testing, 40% of pediatric and 37% of adult neurologists prescribed either calcium or vitamin D. However, only 9% of pediatric and 7% of adult neurologists prescribed prophylactic calcium or vitamin D for patients taking AED therapy.

Reports

Duus ⁷³ reported a case of several severe fractures in a patient following epileptic seizures. The patient had epileptic osteomalacia and responded well to vitamin D treatment.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing anticonvulsant medications are advised to coadminister calcium (200-400 mg three times daily) and vitamin D (200-400 IU twice daily) if the course of treatment is expected to last more than 1 month. Pretreatment and posttreatment monitoring of serum 25-OHD and 1,25-OH ² D levels would also identify individuals at risk of treatment-induced and nutritional/sunlight-related deficiencies of vitamin D. With regard to supplementation, calcium needs to be taken at least 2 hours before or 4 hours after the medication to avoid interfering with drug absorption; calcium carbonate should be avoided in favor of another form less likely to impair drug activity. Individuals in growth phases (children and adolescents) are most vulnerable to depletion patterns and resultant bone loss and other potential adverse effects. Furthermore, many individuals with epilepsy, especially children, lead restricted lifestyles and are often institutionalized or under other forms of full-time care. Such individuals not only experience the effects of the pathophysiology on vitamin D metabolism, but also tend to have compromised nutritional status and restricted time outdoors in the sun, especially during winter months. Thus, sunlight represents an effective and low-risk method of supporting vitamin D status. Walking and other simple forms of weight-bearing exercise will also support bone health and increase the efficacy of nutrient enhancement through dietary and supplemental sources.

Concomitant calcium administration carries a low probability of adversely affecting the efficacy of anticonvulsant therapy. Further research is warranted to develop knowledge of this interaction pattern, factors influencing individual susceptibilities, and clinical options for appropriate therapeutic responses.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Mixed

Effect and Mechanism of Action

Simultaneous intake of atenolol or other beta blockers along with calcium salts may inhibit absorption and bioavailability of both substances and reduce plasma concentrations of the medication. ⁷⁴ Long-term coadministration may increase the drug half-life and lead to accumulation.

Research

In a clinical trial involving five healthy subjects, Kahela et al. ⁷⁵ observed that administration of sotalol with a calcium gluconate solution substantially reduces the absorption and bioavailability of sotalol. In a similar experiment involving six healthy subjects, Kirch et al. ⁷⁶ found that oral administration of 500 mg calcium salts (lactate, gluconate, and carbonate) with atenolol (100 mg) reduced plasma levels of atenolol by 51%, and elimination half-life increased to a mean of 11.0 hours (vs. 6.2 hours with atenolol alone). The prolongation of elimination half-life induced by calcium coadministration led to atenolol cumulation during a subsequent 6-day course. Furthermore, exercise tachycardia was lower 12 hours after atenolol and calcium than with atenolol alone. Gugler and Allgayer ⁵³ reported that later pharmacokinetic research involving calcium antacids did not confirm an interaction with atenolol.

Direct evidence is lacking demonstrating any interaction between calcium and other systemic beta blockers.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing atenolol or related beta blockers should advise patients to separate intake of the medication by at least 1 hour before or 2 hours after calcium supplements (or antacids). Prudence also suggests that physicians check the blood pressure of such patients before and after the initiation of calcium administration during beta-blocker therapy.

Well-designed clinical trials using specific forms of calcium are warranted to determine patterns of interaction, factors influencing clinical significance, and clinical responses to ensure efficacy of both beta blockers and calcium supplementation.

See Cholestyramine, Colestipol, and Related Bile Acid Sequestrants.

	Beneficial or Supportive Interaction, Not Requiring Professional Management
	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Emerging or Consensus

Effect and Mechanism of Action

The ability of bisphosphonates to effectively inhibit osteoclastic activity and bone resorption, maintain healthy bone mineralization, and produce substantial gains in bone mass depends on the presence of adequate vitamin D and other nutrients (e.g., protein, calcium, phosphorus). ^77,78 Calcium, the principal element in bone, can only be absorbed in the brush border of the intestinal mucosa when vitamin D is present. Notably, bisphosphonates have been used effectively to treat the more resistant cases of vitamin D–induced hypercalcemia.

Research

All currently approved bone-active pharmacological agents have been studied only in conjunction with supplemental calcium; newer anabolic agents increase mineral demand in skeletal tissue and will thus require even higher levels of calcium repletion. ⁷⁹ The consensus underlying the fundamental importance of vitamin D and calcium nutriture is underscored by the observation that when Greenspan et al. ⁸⁰ investigated the relative efficacy of hormone replacement therapy (HRT, conjugated estrogen with or without medroxyprogesterone) plus alendronate, HRT alone, alendronate alone, or placebo on spine and hip BMD in 373 osteopenic elderly women, all subjects received calcium and vitamin D supplements. After 3 years, dual-energy x-ray absorptiometry (DXA) scans showed that participants taking combination therapy had greater improvements in BMD at the hip and spine than did those participants taking HRT or alendronate alone, or placebo, all with calcium and vitamin D.

In an uncontrolled clinical trial involving osteoporosis patients with a poor response to bisphosphonate therapy, Heckman et al. ⁸¹ found that the addition of 25 µg (1000 IU) vitamin D daily to the bisphosphonate regimen resulted in significantly increased BMD of the lumbar spine after 1 year. ⁸¹ In a randomized, double-blind trial involving 48 osteopenic and osteoporotic women, Brazier et al. ⁸² compared one group who received alendronate, 10 mg once daily, along with 500 mg elemental calcium daily and 10 µg (400 IU) cholecalciferol (vitamin D ³ ) twice daily for 3 months, and a second group who received the same dosage of alendronate and calcium but placebo instead of the vitamin D. All subjects had low BMD, serum 25-hydroxyvitamin D ³ (25-OHD, calcifediol) less than 12 µg/L, and dietary calcium intake less than 1 g/day. Although markers of bone remodeling such as serum and urinary CTX and urinary NTX (C- and N-terminal telopeptides of type I collagen) were dramatically and significantly decreased after as soon as 15 days of treatment and remained decreased throughout treatment in both groups, the group also receiving the vitamin D demonstrated a more pronounced effect, particularly after 1 month, for the bone resorption markers serum CTX and urinary NTX. These researchers concluded that coadministration of calcium and vitamin D could be appropriate in elderly women with calcium and vitamin D insufficiencies being treated with alendronate, to achieve rapid reduction of bone loss. ⁸²

Paget's disease is characterized by abnormal osteoclastic bone resorption, and bisphosphonates are powerful and selective inhibitors of osteoclastic bone resorption. In a randomized, placebo-controlled, double-blind study involving 15 patients with Paget's disease, O’Doherty et al. ⁸³ observed that daily 1-hour infusions of alendronate caused small decreases in serum calcium, serum phosphate, and urinary calcium excretion.

Reasner et al. ⁸⁴ observed acute changes in calcium homeostasis as a result of 7 days’ treatment with risedronate. A decrease in serum calcium was accompanied by evidence of inhibition of bone resorption in patients with mild primary hyperparathyroidism, a condition typically characterized by hypercalcemia. Oral calcium partially suppressed serum hyperparathyroid hormone in both controls and subjects receiving risedronate. Although patients treated with risedronate had normal fasting serum calcium levels, serum calcium values in these normocalcemic patients were labile after oral calcium. After administration of 2 g calcium daily, serum calcium levels in risedronate-treated patients were similar to those in untreated patients with primary hyperparathyroidism. The authors interpreted these findings to suggest that serum calcium levels are likely to fluctuate in risedronate-treated patients with normal fasting serum calcium during postprandial periods. Further long-term research is warranted to determine whether the lability in serum calcium observed in the short term has clinical significance, how risedronate would influence serum calcium levels and BMD with extended use, and what clinical implications would be for concomitant calcium.

Some patients with prostate carcinoma and a diffuse metastatic invasion of the skeleton exhibit indirect biochemical and histological indications of osteomalacia. Bisphosphonates are known to cause symptomatic hypocalcemia in prostate cancer patients with diffuse skeletal metastases. Bisphosphonate administration can aggravate osteomalacia and give the appearance of symptomatic hypocalcemia because of the transient, striking prevalence of osteoblastic activity over bone resorption by osteoclasts, which are inhibited by bisphosphonate drugs. Calcium supplementation is often considered as contraindicated in individuals with prostate cancer. However, concomitant use with bisphosphonates has been proposed as a means of inhibiting osteoclastic activation that often precedes the abnormal osteoblastic bone formation within metastases. Thus, Adami ⁸⁵ suggested that coadministration of high doses of calcium with alendronate therapy in prostate cancer patients with bone metastases (with evidence of osteomalacia) might contribute to improved clinical outcomes.

In regard to men with nonmetastatic prostate cancer, findings from a small, randomized, double-blind controlled trial conducted by Nelson et al. ⁸⁶ showed that treatment with 70 mg alendronate weekly, plus daily calcium and vitamin D, reversed bone loss in men receiving antiandrogen therapy. In contrast, the 56 subjects taking placebo, calcium, and vitamin D lost BMD during the same period. Notably, among these 112 men, average age 71, only 9% had normal bone mass, whereas 52% had low bone mass and 39% developed osteoporosis after an average 2 years of androgen-deprivation therapy (ADT). ⁸⁶

In a nonblinded, randomized prospective trial examining BMD in 211 long-term adult renal transplant recipients, Jeffery et al. ⁸⁷ compared calcitriol and alendronate and found that osteopenia or osteoporosis, which are experienced by the majority of such patients, can be effectively treated with calcium plus calcitriol or alendronate.

In a randomized trial involving 154 patients with Crohn's disease, Siffledeen et al. ⁸⁸ investigated the efficacy of etidronate plus calcium and vitamin D for treatment of low BMD. The subjects, most of whom had T scores in the osteopenic range (−1.5 to −2.5), were administered etidronate (400 mg orally) or placebo for 14 days, and then both groups were given daily calcium (500 mg) and vitamin D (400 IU) for 76 days in a treatment cycle repeated every 3 months for 2 years. After 24 months, BMD at the lumbar spine, ultradistal radius, and trochanter sites, but not the total hip, increased steadily, significantly, and similarly in both treatment arms. The findings from this trial demonstrate that, in patients with low BMD on absorptiometry, treatment with calcium and vitamin D alone will increase bone density by about 4% per year and that adding etidronate to the treatment program does not appear to enhance the effects of calcium and vitamin D. ⁸⁸ In an accompanying editorial on the preeminence of calcium and vitamin D in limiting fracture risk in Crohn's (inflammatory bowel) disease (IBD), Bernstein ⁸⁹ commented that this study provides reassurance that bisphosphonates are “rarely needed in IBD patients most of whom have T scores greater than −2.5, and many of whom are using corticosteroids to some extent.”

The National Osteoporosis Risk Assessment (NORA) Study, a longitudinal, observational study of osteoporosis among postmenopausal women in primary care practices across the U.S., reported in 2005 that 58% of women who might benefit from the osteoporosis treatment do not receive any of the standard medications, and when HRT is included, the number falls to 38%. ⁹⁰

Reports

In a review of 63 cases, Ruggiero et al. ⁹¹ described a pattern of osteonecrosis of the jaw (ONJ), an otherwise rare condition, in patients undergoing prolonged treatment with bisphosphonates. Fifty-six patients had received intravenous bisphosphonates for at least 1 year, and seven patients were receiving chronic oral bisphosphonate therapy. Fifty-five of these patients were being treated for various forms of cancer, one for osteoporosis. ONJ has occurred spontaneously in a significant number of patients. However, most cases have been associated with infections after dental surgeries, in patients on bisphosphonate therapy. The authors recommend that all patients on long-term bisphosphonate therapy have two or three preventive dental visits per year, and that physicians be watchful for any early signs of ONJ, such as tooth pain, swelling, numbness of the lip and chin, or pain in the jaw.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Calcium and vitamin D are essential for maintaining bone mass and density and imperative to the success of drug therapies for inducing bone augmentation. ⁷⁸ Deficiencies of both nutrients are common in the patient populations at highest risk for bone loss. The importance of exercise and sound nutrition (including adequate protein, calcium, and phosphorus intake) as foundational cannot be overemphasized and is supported by growing evidence. Calcium has a clearly demonstrated effect of enhancing estrogen's effects on bone metabolism. Further, most research indicates that consistent exposure to sunlight (excluding winter in northern latitudes) provides a safe and effective, as well as otherwise beneficial, method of elevating vitamin D levels. Daily doses of 1500 mg calcium and 800 IU vitamin D provide prudent nutritional support for osteoporosis prevention and treatment, or more exactly, 30 to 40 mmol calcium with sufficient intake vitamin D daily, to maintain serum 25(OH)D levels above 80 nmol/L (∼30 µg/L). ⁷⁹

Thus, a synergistic combination of oral calcium and vitamin D, within the context of an active lifestyle and nutrient-rich diet, constitutes the core proactive intervention within integrative therapeutics for all individuals at high risk for osteoporosis, or a foundational treatment for diagnosed bone loss. Notably, low serum vitamin D levels have been associated with the incidence of falls in older women, ⁹² and vitamin D has been found to be helpful in reducing the incidence of falls, a major factor in fracture risk, by improving muscle strength, walking distance, and functional ability. ⁹³ Also, hormone supplementation or replacement regimens (conventional HRT, bio-identical estrogens/progesterone, herbal hormone precursors/modulators) should be considered if indicated in women. In addition to these primary and secondary therapies, the use of a bisphosphonate can provide a potent intervention in reversing bone loss and supporting healthy bone mass.

Coadministration of bisphosphonates and calcium in patients with Paget's disease or prostate carcinoma requires close supervision and regular monitoring within the context of an integrative team of health care professionals trained and experienced in multidisciplinary therapeutics, including conventional pharmacology and nutritional therapeutics.

Oral calcium preparations need to be taken at least 2 hours before or after the bisphosphonate to avoid pharmacokinetic interference. However, the timing of oral vitamin D intake need not be managed because no evidence has indicated potential pharmacological interference with bisphosphonates or other components of the treatment. It is generally recommended to take alendronate or etidronate with a full glass (6-8 ounces) of plain water on an empty stomach and to avoid the recumbent position for at least 30 minutes to prevent potential severe esophageal irritation associated with incomplete transfer of the tablet to the stomach.

Beneficial or Supportive Interaction, with Professional Management

Emerging or Consensus

Effect and Mechanism of Action

Calcitonin is a polypeptide hormone made by the thyroid gland that decreases bone resorption and reduces bone loss. Adequate calcium intake appears to enhance the bone-sparing benefit of calcitonin, particularly on the spine.

Research

Nieves et al. ⁹⁴ reviewed six published clinical trials evaluating the effects of 200 IU intranasal salmon calcitonin in combination with calcium administration (total 1466 mg/day) as well as one using calcitonin alone. They observed that bone mass of the lumbar spine increased 2.1% with calcitonin and calcium, compared with −0.2% per year in those receiving calcitonin alone. These researchers concluded that the available data suggest that a high calcium intake potentiates the positive effect of calcitonin on bone mass of the spine. They also noted that these findings suggest that the dosage of nasal calcitonin used (200 IU) may be suboptimal.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing intranasal calcitonin for prevention or treatment of osteoporosis are advised to coadminister calcium (400-500 mg three times daily).

Potentially Harmful or Serious Adverse Interaction—Avoid

Consensus

Effect and Mechanism of Action

Concomitant use of calcium supplements during calcium acetate administration can produce an additive effect that may be harmful in some individuals, especially in the context of renal failure.

Calcium acetate supplies an extremely bioavailable source of calcium because it ionizes readily and the acetate is quickly burned in the Krebs cycle, thereby providing a ready supply of calcium ions to complex with free phosphorus in renal patients with hyperphosphatemia. Care must be taken not to administer calcium if the serum calcium times phosphorus (Ca×PO ⁴ ) product is greater than 70; calcium phosphate deposition in soft tissues is likely at this level. Aluminum salts were previously used for this purpose but were largely replaced by calcium acetate as the toxicity of aluminum became recognized.

Research

Although the additive interaction between these agents is considered formulaic and highly probable to result in clinically significant adverse effects, evidence from clinical trials focused directly on this interaction is lacking.

Clinical Implications and Adaptations

Physicians prescribing calcium acetate are advised to be watchful for indications of hypercalcemia (e.g., anorexia, depression, poor memory, muscle weakness), monitor serum calcium and phosphorus levels, and warn patients to avoid calcium supplementation. This interaction may be relevant only to the population with chronic renal insufficiency. It is not known whether it applies to those with normal renal function because clinical trials addressing this question are lacking. The probability of a clinically significant interaction involving hypercalcemia after concomitant intake of calcium acetate and other calcium supplements in normal individuals is low.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Preliminary or Emerging

Effect and Mechanism of Action

The primary effect on calcium levels may be caused by lowered absorption of vitamin D under the influence of bile acid sequestrants. Medications in this class can bind calcium and thereby impair its absorption; they may also increase the loss of calcium in the urine.

Research

Diminished intestinal absorption of vitamin D, osteomalacia, and other metabolic alterations have been reported with long-term use of bile acid sequestrants. Colestipol lowers vitamin D absorption and thus adversely affects calcium metabolism. In vitro research indicates that cholestyramine causes appreciable binding of calcium (from calcium chloride) and thereby decreases absorption. ⁹⁵ Animal studies suggest that cholestyramine may deplete calcium (and zinc). Watkins et al. ⁹⁶ observed that rats fed cholestyramine for 1 month had a net negative balance for calcium, increased urinary excretion of calcium and magnesium, and a lower net positive balance for magnesium, iron, and zinc than the controls. They attributed these alterations in calcium, magnesium, and zinc metabolism to impaired vitamin D absorption from the intestine, followed by increased PTH secretion.

One study investigating possible malabsorption of minerals and vitamins in young patients with familial hypercholesterolemia after 5 years of colestipol therapy found no significant changes in plasma levels of calcium, PTH, and vitamin D, as well as other nutrients. However, changes in most of these parameters would not be predicted, and potential effects on bone mass were not assessed. ⁹⁷ However, Tonstad et al. ⁹⁸ conducted a study of 37 boys and 29 girls age 10 to 16 years with familial hypercholesterolemia, first in an 8-week, double-blind, placebo-controlled protocol, then in open treatment for 44 to 52 weeks. After 1 year of colestipol, those who took 80% or more of the prescribed dose had a greater decrease in serum 25-OHD levels than those who took less than 80%. Secondary effects on calcium metabolism and bone health were not investigated directly, but the observed adverse effect on vitamin D would be predicted to impair calcium absorption. Also, levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing bile acid sequestrants are advised to recommend supplementation with calcium (500 mg twice daily) along with vitamin D and other fat-soluble nutrients. Although modest supplementation with vitamin D (10-20 µg or 400-800 IU daily) may be advisable for many individuals, particularly those at high risk for deficiency sequelae, consistent exposure to sunlight (without sunscreen) may be sufficient to maintain healthy vitamin D levels and can be combined with the exercise usually critical to those being prescribed bile acid sequestrants. Exposure to sunlight in the winter months of northern latitudes, however, is likely to be insufficient to maintain adequate vitamin D levels, making it necessary to use dietary supplements or a rich natural source of vitamin D, such as cod liver oil, at least 2 hours before or after the bile sequestrant agents.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern
	Prevention or Reduction of Drug Adverse Effect

Consensus

Effect and Mechanism of Action

Corticosteroids can impair calcium absorption and interfere with both calcium and vitamin D metabolism, thereby adversely affecting bone density and potentially other calcium-related functions. Several mechanisms have been implicated in these adverse effects. Corticosteroids interfere with the activation of vitamin D and thereby impair calcium absorption and contribute to secondary hyperparathyroidism. Decreases in tubular calcium reabsorption with increases in urinary excretion of calcium have also been demonstrated. Thus, increased bone resorption is caused by decreased calcium absorption and increased urinary calcium excretion, leading to secondary hyperparathyroidism. Furthermore, corticosteroids increase the risk for developing osteoporosis not only by altering normal calcium metabolism, but also by reducing osteoblast activity. Also, steroids, even in low dose, can decrease osteocalcin, P1CP, and ALP. ^99-112

Research

Oral corticosteroids can adversely affect BMD and increase the risk of osteoporosis through their impact on both calcium and vitamin D. Numerous studies have demonstrated adverse effects on vitamin D and its functions due to steroid therapy; these are reviewed in the vitamin D monograph. Under active transport conditions, administration of corticosteroids produces a decrease of net calcium absorption by depressing vitamin D–dependent intestinal calcium absorption and increasing vitamin D–independent calcium backflux. ^{101,102,109,113}

Corticosteroids can adversely affect both bone formation and resorption. Serum osteocalcin, a sensitive marker of bone formation (and a vitamin K–dependent protein), is reduced with both short-term and chronic glucocorticoid treatment, corresponding to observed effects of reduced bone formation. In a double-blind placebo-controlled study involving 15 normal subjects, Nielsen et al. ¹⁰⁶ found that oral prednisone at two dosage levels, 2.5 mg and 10 mg, proportionately inhibited serum osteocalcin levels within 3 to 4 hours and even reversed the normal nocturnal rise within the circadian rhythm of serum osteocalcin levels. In a 1998 study, Lems et al. ¹¹² reported that low-dose (10 mg/day) prednisone (LDP) treatment led to a decrease in osteocalcin, P1CP, and ALP and an increase in urinary excretion of calcium. They concluded that LDP has a negative effect on bone metabolism because bone formation decreased and bone resorption remained unchanged or decreased slightly.

A strong trend in the cumulative research findings demonstrates that corticosteroids, especially long-term therapy or repeated use, can reduce bone density, cause development of corticosteroid-induced osteoporosis, and increase the risk of sustaining osteoporotic fractures. ^110,114-118 By comparing asthmatic patients receiving long-term glucocorticoid therapy with a second group of age-matched and gender-matched asthmatic individuals not receiving these drugs, Reid et al. ¹¹⁵ measured a significant reduction in renal tubular calcium reabsorption in the glucocorticoid-treated patients. Tsugeno et al. ¹¹⁷ measured relative cortical volume (RCV) and other parameters in 86 postmenopausal asthmatic women taking high-dose oral steroid (>10 g cumulative oral prednisolone) and 194 age-matched controls. Individuals treated with high doses of oral steroid demonstrated a significantly increased risk of fracture compared with control women after adjustment was made for years since menopause, body mass index, and RCV. In a study involving 117 patients taking oral corticosteroids for chronic lung disease, Walsh et al. ¹¹⁹ found that 58% had osteoporosis (a T score of less than −2.5) and 61% had a vertebral fracture, and that cumulative prednisolone dose was strongly associated with vertebral fracture. After analyzing the composite data, they concluded that “cumulative prednisolone dose is strongly related to fracture risk, and this effect is independent of its more modest impact on BMD.” In a retrospective, cohort study, Steinbuch et al. ¹²⁰ observed that oral glucocorticoid use is associated with an increased risk of fracture. Specifically, they found that dose dependence of fracture risk was observed for hip, vertebral, nonvertebral, and any fractures. Extended duration and continuous pattern of steroid use demonstrated a fivefold increase in risk of hip fracture and 5.9-fold increase in risk of vertebral fracture. Together, the combined effect of higher dose, longer duration, and continuous pattern further increased relative risk estimates to sevenfold for hip fractures and seventeenfold for vertebral fractures. Thus, a consensus has emerged confirming a strong association between oral corticosteroid therapy, especially chronic or repeated use, and adverse effects on calcium balance, BMD, and fracture susceptibility. Vitamin D deficiency is also associated with increased fracture risk as well as risk of falls. Overall, the degree of bone loss usually parallels the cumulative corticosteroid dose, and the highest rate of bone loss is observed in the first 3 to 6 months of therapy.

The adverse effects associated with inhaled corticosteroids (ICs) are generally considered as less common, less severe, and significantly less likely risk to contribute to fractures. For example, in a group of postmenopausal women, Elmstahl et al. ¹²² found no difference in BMD between the subset using ICs and unexposed control subjects, and no dose-response relationship between IC therapy and BMD.

The predominant weight of evidence suggests that coadministration of calcium and vitamin D can mitigate and possibly reverse loss of bone density and risk of osteoporosis associated with long-term oral corticosteroid therapy. In particular, the adverse effects of glucoactive corticosteroids on intestinal calcium transport and bone turnover can usually be counteracted by the combined administration of supplemental doses of calcium and physiologic doses of 25(OH)D ³ . ^102,123,124 Reid and Ibbertson ¹²⁵ studied the metabolic effects of administering 1 g of elemental calcium daily in 13 steroid-treated patients. After 2 months, they concluded that “calcium supplementation suppresses bone resorption without detectable suppression of indices of bone formation” and was therefore likely to result in increased bone mass. In a 2-year, randomized, double-blind, placebo-controlled trial involving 96 patients administered low-dose prednisone (mean dosage, 5.6 mg/day) for rheumatoid arthritis, Buckley et al. ¹¹³ found that subjects who received concomitant calcium carbonate (1000 mg) and vitamin D ³ (500 IU) daily maintained their bone density and gained BMD in the lumbar spine and trochanter. Subsequently, in a multiphase observational trial involving eight healthy, young male volunteers administered low-dose prednisone (10 mg/day), Lems et al. ¹²⁶ found PTH (insignificantly) increased during prednisone (+19%) and prednisone plus 500 mg/day calcium (+14%), but decreased during supplementation with calcitriol (−16%) and calcium/calcitriol (−44%). The increase in PTH during prednisone could be prevented by coadministration of calcitriol and calcium.

Several recent reviews have come to somewhat divergent conclusions. Amin et al. ¹²⁷ conducted a meta-analysis of all randomized controlled trials lasting at least 6 months (and reporting extractable results). They applied change in lumbar BMD as the primary outcome measure and observed that coadministration with the combination of calcium and vitamin D provided a “moderate beneficial effect,” compared with placebo or calcium alone, in protecting against corticosteroid-induced osteoporosis. They concluded that “treatment with vitamin D plus calcium, as a minimum, should be recommended to patients receiving long-term corticosteroids.” In contrast, in a review of the evidence on calcium supplementation for corticosteroid-induced bone loss during steroid therapy, also published in 1999, Adachi and Ioannidis ⁶⁰ declared, “Calcium prophylaxis alone, when patients start corticosteroids, is associated with rapid rates of spinal bone loss and offers only partial protection from corticosteroid-induced spinal bone loss. Though calcium supplementation may have some benefit, it clearly cannot completely prevent corticosteroid-induced bone loss.” Commenting on studies showing benefit from calcium supplementation, they also observed that “caution should be taken when interpreting these results, since bone loss generally tapers or plateaus after the first 12 months of corticosteroid treatment; as such, any therapy might show benefit.” They also questioned the methodology used in assessing bone density, particularly measurements at the radius rather than the spine. They also questioned the adequacy of calcium and vitamin D in counteracting the bone loss caused by corticosteroids and suggested the need for further support, including activated vitamin D. ⁶⁰ In a 2000 Cochrane review, Homik et al. ¹²⁸ evaluated five trials (totaling 247 patients) for lumbar and radial bone BMD after a minimum of 2 years supportive treatment. Their meta-analysis demonstrated “a clinically and statistically significant prevention of bone loss at the lumbar spine and forearm with vitamin D and calcium in corticosteroid treated patients.” Noting the low cost and limited toxicity, they recommended that “all patients being started on corticosteroids should receive prophylactic therapy with calcium and vitamin D.”

The issue of which forms of calcium and vitamin D provide the most effective protection with the least risk of adverse effects remains unresolved. Evidence is lacking from well-designed trials focusing on which of the of various forms of calcium, or combinations thereof, is most efficacious against steroid-induced bone loss, establishing appropriate dosage level, and determining possible variables in patient characteristics influencing efficacy. The question of safety and efficacy in selecting an appropriate form of vitamin D is similarly unresolved and remains contentious within conventional medicine. Numerous researchers and commentators have voiced concern over the risk of hypercalciuria and hypercalcemia when coadministering both calcium and vitamin D and noted experiences or cited reports of such. ¹¹¹ Although the weight of evidence indicates that calcitriol (1,25-OH ² D ³ ), the most active form of vitamin D, may be the most effective, it also carries greater risk than calcifediol (25-OHD) or other forms of vitamin D. ¹²⁹

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The primary concern regarding calcium in the context of corticosteroid therapy is bone loss through decreased absorption and increased urinary excretion. Corticosteroid-induced osteoporosis is a serious disorder that results in significant long-term morbidity. Optimal management strategies to prevent bone loss should include the use of the lowest efficacious dose of steroid medications and shortest duration of administration.

Prevention of adverse effects should include adequate calcium intakes from dietary and supplemental sources totaling 1000 to 1500 mg of calcium daily in conjunction with at least 500 IU of vitamin D daily, although much higher doses may be necessary in the context of a preexisting 25-OHD deficiency. ⁴¹ Monitoring serum levels of both 25-OHD and 1,25-OH ² D (activated form of vitamin D) is appropriate, and prescription of calcitriol may be necessary if a deficiency is indicated. If 25-OHD levels are low (<50 nmol/L), correction with up to 7000 IU vitamin D ³ daily, or 50,000 IU vitamin D ² weekly, for 1 to 2 months will correct the 1,25-dihydroxycholecalciferol level in patients with normal renal function. Often the 1,25-OH ² D level is maintained, even in the face of a 25-OHD deficiency, due to increased secretion of PTH, which speeds up renal conversion of 25-OHD to the active form. Thus, measuring intact PTH as well as both forms of vitamin D provides the most complete picture of vitamin D status. ⁴¹ It is also prudent to monitor for hypercalciuria and hypercalcemia when supplementing with both calcium and vitamin D. Physicians prescribing steroids for longer than 2 weeks should encourage all patients to modify their lifestyles, including smoking cessation and limitation of alcohol consumption. The importance of mild to moderate weight-bearing exercise cannot be overemphasized; 30 minutes to 1 hour every day, particularly with sunlight exposure, should be strongly encouraged, if feasible. However, individuals with known or potential bone loss should be advised to develop an exercise program under the supervision of a physician or other health care professional familiar with the increased risks of fracture associated with long-term use of steroids.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Minimal to Mild Adverse Interaction—Vigilance Necessary

Consensus

Effect and Mechanism of Action

EDTA binds to calcium and thereby increases calcium excretion.

Research

The chelation function of EDTA is central to its primary pharmacological action in therapeutic application. ¹³⁰ As such, chelation with EDTA is considered among standard causes of hypocalcemia from increased loss of calcium, and EDTA is used experimentally to induce hypocalcemia. ¹³¹ However, in the presence of heavy metals, which bind more tightly to EDTA than calcium, the heavy metals will preferentially bind.

Experiments by Foreman and Trujillo ¹³² (1954) found that EDTA demonstrated 45% to 72% efficiency chelating Ca ⁺⁺ and that up to 3.2 mg/dL Ca ⁺⁺ is bound during infusion. Calcium excretion changed over time after chelation, with 28% excess Ca ⁺⁺ excreted during infusion, 60% excess Ca ⁺⁺ excreted 6 hours after infusion, and 12% excess Ca ⁺⁺ excreted 6 to 12 hours after infusion. Overall, serum ionized Ca ⁺⁺ was significantly reduced. Numerous responses to EDTA-induced hypocalcemia have been documented, including ionization of protein-bound and soft tissue Ca ⁺⁺ , induction of PTH secretion and vitamin D ³ synthesis, stimulation of bone resorption and osteoclast differentiation, and suppression of osteoblast differentiation.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Chelation with EDTA or other agents requires appropriate training and proper monitoring. Assessment of calcium levels is appropriate, and clinical responses will vary accordingly. When properly administered, EDTA chelation is considered unlikely to result in adverse reactions from hypocalcemia. Physicians who administer EDTA for chelation of heavy metals or other clinical applications routinely supplement their patients with minerals of nutritional importance.

	Beneficial or Supportive Interaction, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect

Effect and Mechanism of Action

Estrogen-containing medications can contribute to decreased BMD and increase the long-term risk of osteoporosis. Concomitant use of calcium (and vitamin D) supplements and exogenous estrogen may act synergistically to improve bone density and support the prevention and treatment of osteoporosis. Calcium, the principal element in bone, can only be absorbed in the brush border of the intestinal mucosa when vitamin D is present. Estrogen appears to enhance calcium absorption by increasing serum 1,25-dihydroxycholecalciferol [1,25(OH) ² D]. In contrast to the beneficial effect on vitamin D (and calcium) metabolism exerted by estrogens, progestins may diminish that benefit. Estrogens may also contribute to an overall increase in calcium blood levels by decreasing urinary calcium loss. Overall, the ability of exogenous female hormones, particularly forms of estrogen, to effectively inhibit osteoclastic activity and bone resorption, maintain healthy bone mineralization, and support bone mass is inherently dependent on the presence of vitamin D, calcium, and other nutrients (e.g., protein, phosphorus). ^77,78

Research

In a randomized clinical trial, Teegarden et al. ¹³³ studied the relationship between dietary calcium intake and BMD in 133 young women (18-30 years old) using oral contraceptives (OCs) who all were initially characterized by dietary calcium intake of less than 800 mg/day. The subjects were assigned to groups stratified by dietary intake: high calcium intake (1200-1300 mg/day), medium calcium intake (1000-1100 mg/day), and control (<800 mg/day). They found that higher levels of calcium intake, in the form of dairy products, positively impacted percent change of total-hip and total-body bone mineral density (BMD) and bone mineral content (BMC) and that such intake patterns “prevented a negative percent change in total hip and spine BMD” in women using OCs. They concluded: “Dairy product intake, at levels to achieve the recommended intakes of calcium, protected the total hip BMD and spine BMD from loss observed in young healthy women with low calcium intakes who were using [OCs].” ¹³³

The negative calcium balance usually associated with aging is accentuated in osteoporotic women who have decreased calcium absorption and decreased serum levels of 1,25(OH) ² D. In a controlled trial involving 17 women with surgically induced menopause, Lobo et al. ¹³⁴ (1985) observed that serum levels of 1,25(OH) ² D increased and urinary calcium loss decreased after 2 months of conjugated estrogens (0.625 mg daily). ¹³⁴ Subsequently, several studies have investigated whether such elevated vitamin D levels might correspond with increased bone strength and reduced risk of fractures, and how such effect might vary given initial BMD status, for different individuals, under different HRT regimens, or with different forms of calcium.

Several studies have examined the role of estrogen in improving calcium balance in women with postmenopausal osteoporosis. In a randomized, double-blind, placebo-controlled trial involving 128 healthy Caucasian women over age 65 with low spinal BMD, Recker et al. ¹³⁵ compared parameters of BMD and bone loss under continuous low-dose HRT (conjugated equine estrogen, 0.3 mg/day, and medroxyprogesterone, 2.5 mg/day) in conjunction with calcium and vitamin D versus placebo. Subjects in both groups were administered sufficient calcium to bring all calcium intakes above 1000 mg/day and oral 25-hydroxyvitamin D sufficient to maintain serum 25-OHD levels of at least 75 nmol/L. Through the course of 3.5 years of observation, significant increases were seen in spinal BMD as well as in total-body and forearm bone density, particularly among patients with greater than 90% adherence to therapy. Meanwhile, breast tenderness, spotting, pelvic discomfort, mood changes, and other symptoms typically associated with HRT were mild and short-lived under this relatively low-dose regimen. These authors concluded that “continuous low-dose HRT with conjugated equine estrogen and oral medroxyprogesterone combined with adequate calcium and vitamin D provides a bone-sparing effect that is similar or superior to that provided by other, higher-dose HRT regimens in elderly women” and is well tolerated by most patients. ¹³⁵

In a 6-month placebo-controlled clinical trial involving 21 postmenopausal women with osteoporosis, Gallagher et al. ¹³⁶ observed that conjugated equine estrogen increased both calcium absorption and serum vitamin D levels [1,25-(OH) ² D]. Subsequently, these researchers investigated the roles of estrogen deficiency and declining calcium absorption caused by reduced activated vitamin D (calcitriol) levels or intestinal resistance to calcitriol as central factors in age-related bone loss. In a randomized, double-blind, placebo-controlled trial involving 485 elderly women (age 66-77) with normal bone density for their age, they compared the effects of estrogen replacement therapy (ERT, 0.625 mg conjugated estrogens daily for women without a uterus) and HRT (ERT plus 2.5 mg medroxyprogesterone acetate daily for women with a uterus) with or without calcitriol (1,25-OHD) versus placebo. HRT alone and in combination with calcitriol were both highly effective in reducing bone resorption and increasing BMD at the hip and other key sites. In particular, calcitriol was effective in increasing BMD in the femoral neck and spine. In the adherent women, the combination of ERT/HRT and calcitriol increased BMD in the total hip and trochanter significantly more than did ERT or HRT alone, particularly in women who were adherent to treatment. ¹³⁷

Among several benefits observed in perimenopausal and postmenopausal women, calcium coadministration enhances the beneficial effect of exogenous estrogen on bone mass. ^138,139 Nieves et al. ⁹⁴ reviewed and analyzed 31 published clinical trials that measured bone mass of postmenopausal women from at least one skeletal site and determined that high calcium intake from diet or supplements potentiates the positive effect of estrogen on bone mass at all skeletal sites. In a retrospective study involving 315 women, Pines et al. ¹⁴⁰ observed that early postmenopausal women taking calcium supplements with estradiol (or conjugated estrogens) demonstrate significantly greater gains in BMD than women taking HRT alone and concluded that calcium supplementation should be recommended in all postmenopausal women. In a placebo-controlled randomized trial involving 63 postmenopausal women, Ruml et al. ¹⁴¹ found that calcium citrate (400 mg twice daily) averted bone loss and stabilized BMD in the spine, femoral neck, and radial shaft in women relatively soon after menopause. They attributed this bone-sparing action to the inhibition of bone resorption from PTH suppression.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Calcium intake, along with vitamin D, remains the fundamental component supporting bone health at all ages and for both genders and is of particular importance in preventing bone loss in postmenopausal women. Requirements for healthy calcium intake begin at an early age because OC use may prevent attainment of maximal peak bone mass in young women. For women in postmenopausal years, HRT has been the mainstay of osteoporosis prevention but is limited because of dose-related risks, adverse effects, and patient acceptance. Estrogen may improve calcium absorption, vitamin D activity, and bone metabolism, but it remains important for women taking estrogen to maintain adequate calcium intake through diet and supplementation. Deficiencies of both nutrients are common in the patient populations at highest risk for osteoporosis. Calcium and estrogen have a clearly demonstrated synergistic effect of enhancing each other's effects on bone metabolism. Nevertheless, prudent nutritional support for osteoporosis prevention and treatment can be provided through diet or supplementation including 1500 mg/day of calcium and 800 IU (20 µg) vitamin D, or more exactly, sufficient intake vitamin D per day to maintain serum 25(OH)D levels above 80 nmol/L (30 ng/ml or µg/L). ⁷⁹

Thus, a synergistic combination of oral calcium and vitamin D, within the context of a calcium-rich diet and an active lifestyle, constitutes the core proactive intervention within integrative therapeutics for all women using exogenous estrogens, particularly individuals at high risk for osteoporosis, or a foundational treatment for diagnosed bone loss. Additionally, in the treatment of menopausal women, hormone supplementation or replacement regimens (conventional HRT, bio-identical estrogens/progesterone, isoflavones, herbal hormone precursors/modulators) may achieve similar effects, but conclusive evidence is lacking; further research through well-designed clinical trials is warranted. Bisphosphonates and calcitonin, as well as magnesium, boron, and other nutrients, may also play a role as options within a comprehensive approach to bone health through the later phases of the life cycle in both women and men.

The importance of exercise and sound nutrition as foundational cannot be overemphasized and is supported by growing evidence. Weight-bearing exercise is fundamental to maintaining BMD and reducing bone loss. ^142-144 Vitamin D nutriture and adequate protein and phosphorus intake are also essential. Further, most research indicates that consistent, moderate exposure to sunlight provides a safe and effective, as well as otherwise beneficial, method of elevating vitamin D levels. Ultimately, prevention through exercise and calcium intake during the life stage of skeletal development is most important for establishing peak bone density. Patients should be educated and encouraged to make these lifelong habits.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Effect and Mechanism of Action

The 3-carbonyl and 4-oxo functional groups on quinolone antibiotics form a chelate with calcium and other divalent metal cations, such as aluminum, copper, iron, magnesium, manganese, and zinc. This binding process can substantially interfere with the absorption, bioavailability, and activity of both the antimicrobials in this class and the supplemental calcium.

Research

The ability of multivalent cations to reduce the absorption and serum levels of oral quinolone antibiotics is well established. ^145-156 However, much research has involved mineral-based antacids rather than nutritional supplements; the limitations of extrapolating these data have not been analyzed. This interaction appears to have the greatest clinical significance with aluminum and magnesium ions, occurs to a lesser extent with bismuth and calcium ions, and is probably nonexistent with sodium ions. The observed reduction in quinolone absorption can significantly affect peak concentration (C ^max ) and percent bioavailability and in some circumstances will inhibit the therapeutic effectiveness of the antibiotic. Calcium intake appears to affect the rate, but not the extent, of moxifloxacin absorption. ¹⁵⁷ Experimental data indicate that the degree of this interference is variable for different medications, with calcium-containing antacids reducing quinolone bioavailability to the following percentages: lomefloxacin (98%), levofloxacin (97%), ciprofloxacin (59%), and norfloxacin (37%). ^{150,152,154,158-162}

In studies with rats and human volunteers, Sanchez Navarro et al. ¹⁶³ found that coadministration of 500 mg/L calcium carbonate (CaCO ³ ) to healthy volunteers significantly reduced the urinary excretion of 250 mg/L ciprofloxacin, although neither the fraction of absorbed dose nor the half-life was greatly affected. They concluded that calcium therefore shares the same propensity as other cations in impairing the absorption of ciprofloxacin. However, Lomaestro and Bailie ¹⁶⁴ found that repeated doses of calcium carbonate, administered 2 hours before ciprofloxacin, did not significantly alter the relative bioavailability of ciprofloxacin. Pletz et al. ¹⁶⁵ compared the effect different timing of calcium carbonate intake on the oral bioavailability of gemifloxacin. In an experiment involving 16 volunteers, gemifloxacin was administered alone, 2 hours before, simultaneously, or 2 hours after calcium carbonate. Only simultaneous coadministration of calcium carbonate reduced C ^max (−17%) and AUC (−21%) significantly.

Calcium depletion resulting from chelation by this class of medications has not been studied per se. Although plausible, such an adverse effect on calcium balance is highly improbable given the normal physiological controls on blood calcium levels and the limited duration of standard drug use. Long-term quinolone therapy and simultaneous oral intake could theoretically contribute to bone loss.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians treating patients for serious infections with quinolone antibiotics should advise them to refrain from ingesting calcium (and all other divalent mineral cation) supplements during therapy to avoid interfering with the absorption and thus the antimicrobial action of the medication. If this is not possible, administration of the medication 2 hours before or 6 hours after ingestion of an oral calcium supplement is suggested and can effectively minimize risk of an adverse interaction. This recommendation also applies to intake of calcium-containing antacids and calcium-rich or calcium-fortified foods. Monitor for decreased therapeutic effects of oral quinolones if inadvertently administered simultaneously with oral calcium supplements or calcium antacids.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Effect and Mechanism of Action

Cimetidine may significantly decrease net calcium absorption and transport across the intestinal lumen to the mucosa, an action that may be secondary to its effect on the release of parathyroid hormone (PTH) or an effect on vitamin D metabolism.

Inhibition of gastric acid secretion by H ² antagonists or proton pump inhibitors (PPIs), particularly at high doses, can impair calcium absorption and increase risk of fracture(s) since an acidic environment appears to enhance absorption of some forms of calcium. Furthermore, solubility of calcium is highly pH-dependent, particularly as seen in in vitro experiments. PPIs “also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps.” ¹⁶⁶

Research

Human studies have shown that cimetidine can lower the amount of calcium in the body, but the conditions, mechanisms, and clinical significance of this interaction pattern are not yet fully understood. Bo-Linn et al. ¹⁶⁷ developed a method to measure gastrointestinal absorption of calcium after a single meal. Although a large dose of cimetidine significantly reduced gastric acid secretion, it had no effect on calcium absorption in normal subjects and in one patient with diagnosed achlorhydria. This pattern was observed for all the calcium sources investigated: milk, calcium carbonate (CaCO ³ ), and calcium citrate. Furthermore, calcium absorption from calcium carbonate was the same when intragastric contents were relatively acid (pH 3.0) and when acidity was relatively neutral (pH 7.4). A subsequent trial by Recker ¹⁸ found that calcium absorption from calcium carbonate was lower in patients with achlorhydria than in normal subjects. However, when calcium carbonate was taken with a meal, calcium absorption was normal, even in achlorhydric patients. In a review of studies on calcium bioavailability and stomach acid, Wood and Serfaty-Lacrosniere ¹⁶⁸ concluded that the elderly, patients taking high doses of gastric acid–suppressive medications, and fasted individuals can most effectively absorb calcium carbonate ingested with a meal. Similarly, Heaney et al. ²¹ determined that bioavailability of calcium carbonate and calcium phosphate is enhanced when taken with meals.

Ghishan et al. ¹⁶⁹ studied the effect of cimetidine on intestinal calcium transport in a rat model and observed a significant decrease in net intestinal calcium transport. In a double-blind, placebo-controlled crossover study, Fisken et al. ¹⁷⁰ treated eight primary hyperparathyroid patients with cimetidine or placebo for 2 months and reported that serum calcium levels declined significantly in a single patient and that PTH was affected in only one patient. In a clinical trial involving 16 patients with primary hyperparathyroidism treated with 1200 mg cimetidine daily, Caron et al. ¹⁷¹ proposed that the reduced calcium absorption observed with cimetidine may be secondary to the effects of the drug on vitamin D metabolism rather than inhibition of gastric acid secretion.

Kerzner, O’Connell, et al. ¹⁷² conducted a randomized, double-blind, placebo-controlled, crossover trial in which 18 women age 65 and older were administered omeprazole (20 mg daily) or placebo for 7 days, then after a 3-week washout period, switched over to the alternative treatment. On the morning of the seventh day of treatment after an overnight fast, subjects ingested radiolabeled calcium carbonate (500 mg elemental calcium), blood levels of which were measured in samples obtained at time zero and 5 hours later. Each woman also ingested a multivitamin containing 400 units of vitamin D daily throughout the study. The researchers observed that fractional calcium absorption was decreased from an average of 9.1% while treated with placebo to 3.5% with omeprazole. In confirming their hypothesis that omeprazole would alter calcium absorption, the authors added that further trials are needed to “determine whether the body could adapt to this decreased calcium absorption rate and to evaluate other solutions to overcome the omeprazole/proton pump inhibitor–calcium drug-drug interaction.” ¹⁷² In a nested case-control study comparing users of PPI therapy and nonusers of acid suppression drugs who were over age 50, Yang et al. ¹⁶⁶ found that “long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.” Furthermore, use of PPIs for longer than 1 year was associated with increased fracture risk by 44%, and long-term, high-dose users had 2.6 times greater risk than nonusers. However, they added that “short-term PPI use is unlikely to have a significant impact on fracture risk regardless of how high the daily dosage.” The authors noted that PPIs “may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps.”

Physicians experienced in nutritional therapeutics have often contended that gastric acid secretion declines with age in many individuals, and that this contributes to diminished calcium absorption, cumulative negative calcium balance, and eventually bone loss. In a cross-sectional study involving 248 white male and female volunteers age 65 or older, Hurwitz et al. ¹⁷³ reported that “nearly 90% of elderly people in this study were able to acidify gastric contents, even in the basal, unstimulated state. Of those who were consistent hyposecretors of acid, most had serum markers of atrophic gastritis.” Given the mixed evidence, long-term trials investigating this critical issue are warranted.

The relatively short duration of most trials and the utilization of serum calcium levels as a marker of calcium limit the strength of the available evidence in demonstrating a lack of effect on calcium balance over long periods (i.e., the scale of bone loss).

Report

Edwards et al. ¹⁷⁴ reported the case of a 92-year-old woman with a normal serum calcium level who became severely hypocalcemic and exhibited tetany, seizures, and impaired mental status after receiving cimetidine postoperatively. Her condition responded to intravenous diazepam, phenytoin sodium, and parenteral calcium gluconate. Serum calcium levels were maintained by calcium infusions until the cimetidine treatment was stopped. The authors suggested that the effect of cimetidine on serum PTH level may have been responsible for the observed complications.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing H ² antagonists, PPIs, or other medications that reduce gastric acidity can advise patients to use calcium preparations other than calcium carbonate, which can be absorbed effectively when taken away from meals. Periodic assessment of calcium levels and BMD would be prudent in patients receiving chronic gastric acid–suppressive therapy, particularly postmenopausal women.

	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Effect and Mechanism of Action

Over time, heparin causes bone loss, especially in the spine, hips, pelvis, and legs. This effect is more pronounced with standard (unfractionated) heparin (UFH), than with low-molecular-weight heparin (LMWH). At least one mechanism of the negative effect of UFH on bone is nonspecific binding of the longer polysaccharide chains to bone, with inhibition of osteoblastic function. Heparin may also inhibit formation of 1,25-dihydroxyvitamin D by the kidneys. ¹⁷⁵

Research

Majerus et al. ¹⁷⁶ reported that use of heparin, at full anticoagulation doses, for several months has been found to cause osteoporosis. Likewise, both Wise and Hall ¹⁷⁷ and later Haram et al., ¹⁷⁸ found that women who received heparin therapy during pregnancy experienced decreased bone density, or osteopenia. On the other hand, in one study, nine women undergoing heparin treatment received 6.46 g daily of a special calcium preparation, ossein-hydroxyapatite compound (OHC), over 6 months and were compared to 11 women not receiving the bone-protective treatment. In the OHC-group, good compliance was observed, with no side effects and reduced back pain. Those taking the calcium preparation did not demonstrate the expected decreases in bone mass, whereas bone mass dropped significantly in the controls. ¹⁷⁹

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although the adverse effects of heparin on vitamin D, calcium, and bone metabolism are well documented, research confirming the benefits of coadministering calcium and vitamin D in individuals on heparin therapy for any extended period is limited. However, in the meantime, such nutritional support would most likely be beneficial and is not contraindicated. Physicians prescribing UFH may find it prudent to coadminister calcium and vitamin D. With chronic use, the vitamin D metabolite that should be measured to determine vitamin D status is 25(OH)D, which is the major circulating form of vitamin D, circulating at 1000 times the concentration of 1,25(OH) ² D and having a half-life of 2 weeks; after D ³ repletion has been initiated, monitoring l,25(OH) ² D may be adequate. With long-term heparin therapy, assessment of BMD may also be indicated.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Effect and Mechanism of Action

Isoniazid appears to decrease levels of both calcium and vitamin D and may interfere with the activity of both nutrients. Observed declines in activated vitamin D (1α,25-dihydroxyvitamin D) can produce relative hypocalcemia and induce elevation in PTH levels. Isoniazid can inhibit hepatic mixed-function oxidase activity, as evidenced by a reduction in antipyrine and cortisol oxidation, as well as hepatic 25-hydroxylase and renal 1α-hydroxylase; thereby causing such a reduction in the corresponding vitamin D metabolites. ^180,181

Research

Brodie et al. ¹⁸⁰ investigated the effect of isoniazid on vitamin D metabolism, serum calcium and phosphate levels, and hepatic monooxygenase activity by administering isoniazid, 300 mg daily, to eight healthy subjects for 14 days. They observed several responses, including a 47% drop in the concentration of 1α,25(OH) ² D (most active metabolite of vitamin D) after a single dose of isoniazid, with lowered levels continuing throughout the study, declines in levels of 25(OH)D (major circulating form of the vitamin) in all subjects and to below normal range in six, and a 36% elevation in PTH levels in response to the relative hypocalcemia produced. In a study involving 46 children with asymptomatic tuberculosis (TB), Toppet et al. ¹⁸² found that children administered isoniazid for 3 months demonstrated a decrease in blood levels of 1,25(OH) ² D. Isoniazid appears to interfere similarly with the activity of many other nutrients, including magnesium.

Specific evidence is lacking to determine if isoniazid or related agents actually cause symptoms of vitamin D deficiency and calcium depletion, especially with long-term therapy. Clinical trials are warranted to investigate the clinical significance of any depletion pattern and efficacy of prophylactic intervention. Such research is particularly important in children undergoing long-term therapy, in whom potential adverse effects may significantly impair the calcium economy during the critical life stage when maximum bone density is being attained and will be relied on for a lifetime.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing isoniazid or related antitubercular therapy, especially for greater than 1 month, are advised to recommend coadministration of calcium and vitamin D, preferably as part of a multivitamin-mineral formulation (at least 50 mg/day vitamin B ⁶ is indicated with INH as well), as a prudent measure, unlikely to interfere with the efficacy of the medication(s). Calcium in the range of 100 to 250 mg three times daily would be appropriate, but research is lacking to confirm specific effective dosage levels. Such nutrient support may be especially critical for children undergoing long-term therapy.

Concurrent vitamin D administration may be of great value in addition to antituberculous drugs in the treatment of tuberculous children, and its use is highly recommended. ¹⁸³ Exposure to sunlight is the simplest and most natural way to provide activated vitamin D; sunshine and mountain air were characteristic of the great TB sanitoriums in the pre–anti-TB drug era. However, when vitamin D is to be administered orally, the typical dosage would be in the range of 5 to 10 µg (200-400 IU) per day, depending on size and body weight.

Granulomatous lesions, such as those present in extensive TB infection, often contain active 1-hydroxylase enzymes that activate 25-OH cholecalciferol and are independent of the feedback mechanisms that regulate the renal 1-hydroxylase enzymes. Regular monitoring of serum calcium would provide indication of early vitamin D toxicity in this setting. Research findings emphasize the need for regular monitoring of vitamin D status in this population, even if no sign of rickets is observed in these patients.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Effect and Mechanism of Action

Calcium compounds may form chelates with levothyroxine or related thyroid medications in the digestive tract, thereby reducing absorption, bioavailability, and efficacy of both agents. In particular, levothyroxine adsorbs to calcium carbonate in an acidic environment. ¹⁸⁴ Thyroid hormone medications are known to increase calcium excretion. Most researchers agree that the complete mechanism of this interaction is unknown.

Research

Research on the clinical implications of the binding effect between calcium compounds and thyroid hormone medications is inconclusive, mixed, and contradictory. Several studies have found measurable changes in the bone density of women undergoing long-term treatment with thyroxine and other forms of thyroid medication at substitutive or suppressive doses. Controversy surrounds these findings’ interpretation and their implications for bone metabolism. The results of studies examining the influence of T ⁴ therapy on bone mineral density (BMD) may produce conflicting findings, in part, as a reflection of the inclusion of patients with varying thyroid disorders. Apparently the impact of potential calcium depletion is greatest among women with a history of hyperthyroidism and thyrotoxicosis.

In 1988, Paul et al. ¹⁸⁵ cautioned that women treated with L-T ⁴ for extended periods had a 12.8% lower BMD at the femoral neck and a 10.1% lower BMD at the femoral trochanter compared with matched controls. They suggested that excessive dosages of thyroid hormone might play a significant role in the occurrence of such patterns. In 1991, Adlin et al. ¹⁸⁶ noted that long-term L-thyroxine therapy was associated with decreased density of the spine and hip. However, they concluded that because subclinical hyperthyroidism, decreased calcitonin responsiveness, and a history of hyperthyroidism were demonstrated in some or all of these patients, these factors must be considered as possible causes of the decreased BMD. Later in 1991, in a study involving 26 premenopausal women with Hashimoto's thyroiditis receiving long-term physiological doses of levothyroxine replacement therapy, Kung and Pun ¹⁸⁷ observed that, compared with controls, women receiving the levothyroxine treatment had normal total-body BMD levels but had significantly lower BMD levels at the femoral neck (−5.7%), femoral trochanter (−7.0%), Ward's triangle (−10.6%), both arms (right, −7.8%; left, −8.9%), and pelvis (−4.9%). In contrast, lumbar spine BMD levels were similar in the two groups. These researchers concluded that patients receiving physiological doses of levothyroxine may have decreased BMD.

However, the findings of other investigators suggest that, under most circumstances, taking thyroid hormones may not be associated with reduced bone density. Franklyn et al. ¹⁸⁸ compared case-control studies of patients on long-term T ⁴ therapy who had or had not previously received radioiodine treatment for thyrotoxicosis, as well as previously thyrotoxic patients who had not required T ⁴ replacement. After measuring BMD at several sites and comparing results among the three groups, they concluded that thyroxine therapy alone does not represent a significant risk factor for loss of BMD. However, they did note a risk of bone loss in postmenopausal (but not premenopausal) females with a previous history of thyrotoxicosis treated with radioiodine. Thyroid hormone use is much less common in men, who also have less osteoporosis. Schneider et al. ¹⁸⁹ compared BMD at several sites in 33 men taking a mean thyroxine-equivalent dose of 130 µg daily, for an average of 15.5 years, with 653 nonusers; all 685 subjects were Caucasian men age 50 to 98. They found no significant differences in BMD at any site between users and nonusers, before or after controlling for age, body mass index, smoking, thiazide diuretics, and oral corticosteroid use. These authors concluded that long-term thyroid hormone use was not associated with adverse effects on BMD in men. Lopez Alvarez et al. ¹⁹⁰ determined that histological type of thyroid neoplasia, doses of thyroid hormones, thyroid hormone levels, and duration of follow-up were not associated with changes in BMD.

No published findings among the research reviewed demonstrated the appropriateness or efficacy of calcium supplementation for individuals receiving long-term thyroid therapy.

Systematic research on the effect of calcium supplementation on the absorption of thyroid medication is still in preliminary stages. This probable interaction deserves continued investigation because concurrent treatment with both agents is quite common, particularly in peri- and postmenopausal women. Singh et al. ¹⁸⁴ conducted an 8-month prospective cohort study, complemented by an in vitro investigation of T ⁴ binding to calcium carbonate (CaCO ³ ), and found that simultaneous ingestion of 1200 mg/day calcium carbonate and levothyroxine significantly reduced absorption of the thyroid hormone medication and increased serum thyrotropin levels. Mean levels of both free T ⁴ and total T ⁴ were significantly reduced during the calcium period and increased after calcium discontinuation. The in vitro experiment showed that adsorption of T ⁴ to calcium carbonate occurs at acidic pH levels. ¹⁸⁴

Reports

Schneyer ¹⁹¹ reported reduced levothyroxine effectiveness during simultaneous ingestion of calcium formulations in three women with thyroid cancer who were receiving levothyroxine to suppress serum thyroid-stimulating hormone (TSH) levels. In one case, TSH concentrations increased from 0.08 to 13.3 mU/L over a 5-month period during concomitant administration, and returned to normal after discontinuation of the calcium supplement. Separating the doses of levothyroxine (morning) and calcium carbonate (after lunch or dinner) was reported to minimize the effects of the interaction.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

High calcium intake presents a high probability of interfering with the absorption and activity of thyroid hormone medications if taken simultaneously. Physicians prescribing thyroid therapy should advise patients to take the medication 2 hours before or 4 hours after ingestion of an oral calcium supplement (or calcium-rich foods) to effectively minimize risk of the nutrient interfering with the medication. Many patients find it easiest to take their thyroid medication in the morning and their calcium supplement before bedtime. Thyroid functions should be closely monitored in patients receiving long-term levothyroxine treatment.

No conclusive evidence demonstrates calcium depletion and decreased BMD attributable to thyroid hormone therapy, and no firm evidence supports the proposition that additional calcium supplementation is necessary for or even beneficial to individuals taking thyroid medication on a long-term basis. Even so, many health care providers trained in nutritional therapies have suggested the need for additional calcium supplementation by some patients using these drugs. The seemingly inconsistent findings may indicate that the effect of thyroid medications on calcium varies based on the individual's gender, history, condition, menstrual status, and other factors. Precisely because of this patient variability, many practitioners of nutritional medicine advocate the periodic testing of 24-hour urinary calcium levels for individuals using thyroid medication for more than a few months. Bone densitometry should be performed in patients at risk for osteoporosis. Physicians prescribing thyroid medication should discuss with patients their potential need for calcium supplementation beyond what would normally be recommended based on their age, gender, and menstrual status.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Effect and Mechanism of Action

Biguanide therapy, particularly metformin, causes reduced vitamin B ¹² absorption and low serum total vitamin B ¹² and holotranscobalamin (B ¹² -TCII) levels by depressing intrinsic factor secretion ¹⁹² and through a calcium-dependent ileal membrane antagonism affecting B ¹² –intrinsic factor complex uptake. ¹⁹³ Vitamin B ¹² –intrinsic factor complex uptake by ileal cell surface receptors depends on calcium availability, and metformin specifically affects calcium-dependent membrane action; this effect can be reversed by concomitant calcium.

Research

Of patients prescribed metformin, conservatively 10% to 30% have evidence of reduced vitamin B ¹² absorption, accompanied by a decline in folic acid status and elevation of homocysteine (Hcy). An early study by Carpentier et al. ¹⁹⁴ involving diabetic patients determined that whereas biguanides depleted vitamin B ¹² , folic acid was not similarly affected. In a subsequent study involving nondiabetic male patients with coronary heart disease, Carlsen et al. ¹⁹⁵ observed that metformin increases total serum Hcy levels and depletes vitamin B ¹² and sometimes folic acid. ¹⁹⁵ More recently, in a randomized, placebo-controlled trial involving 390 patients with type 2 diabetes, Wulffele et al. ¹⁹⁶ found that 16 weeks of treatment with metformin reduces serum levels of vitamin B ¹² and folate, resulting in a modest increase in Hcy.

Caspary et al. ¹⁹³ initially noted that the vitamin B ¹² malabsorption, pathological Schilling tests, and elevated fecal bile acid excretion observed with biguanides, particularly metformin, improved when the medication was discontinued or antibiotics were administered. They interpreted these findings to suggest that small intestinal bacterial overgrowth, leading to binding of the intrinsic factor–vitamin B ¹² -complex to bacteria, was responsible for the B ¹² depletion observed in diabetic patients on biguanide therapy. Subsequently, Adams et al. ¹⁹² surveyed 46 randomly selected diabetic patients on biguanide therapy and found that 30% demonstrated malabsorption of vitamin B ¹² , apparently by two different mechanisms. On withdrawal of the drug, normal absorption returned in only half of those with malabsorption. Using absorption tests with exogenous intrinsic factor, these researchers further determined that biguanide-induced depression of intrinsic factor secretion mediated the persistent malabsorption in most individuals of the latter group. Bauman et al. ¹⁹⁷ performed a comparative study in which a group with type 2 diabetes who had been receiving sulfonylurea therapy was switched to metformin for 3 months, after which oral calcium was administered. Monthly serial measurements of serum total vitamin B ¹² and B ¹² -TCII revealed parallel declines in those taking metformin compared with controls. The observed depression of B ¹² -TCII was reversed by the introduction of oral calcium supplementation.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing metformin or other biguanides are advised to supplement vitamin B ¹² , folic acid, and calcium and regularly monitor folic acid, vitamin B ¹² , and possibly Hcy levels.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Effect and Mechanism of Action

Sulfonamides, including sulfamethoxazole, can decrease absorption of calcium (as well as magnesium and vitamin B ¹² ) and potentially lead to calcium depletion.

Research

This interaction is considered as well established, although specific evidence from well-designed clinical trials or qualified case reports is lacking.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The probability of adverse effects on calcium balance is low when medications in the sulfonamide family of antibiotics are used for 2 weeks or less. Physicians prescribing sulfamethoxazole or related medications, especially repeatedly or for longer than 2 weeks, are advised to monitor levels of calcium and other potentially affected nutrients and consider supplementation, such as coadministration of 1000 to 1500 mg calcium in divided doses, at least 2 hours before of after the medication.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Effect and Mechanism of Action

Tetracyclines form insoluble chelates with calcium and other polyvalent metal cations, including iron, magnesium, and zinc. ^198,199 Thus, calcium and tetracycline-class antibiotics tend to bind with each other, and absorption of both agents is impaired.

Calcium may impair absorption of tetracycline antibiotics and therefore diminish their effectiveness. Tetracycline-class medications are primarily absorbed in the stomach and upper small intestine. Calcium, as well as dairy products and other foods containing high concentrations of calcium, may decrease the absorption of tetracyclines because of chelate formation in the gut.

Tetracyclines reduce absorption of calcium and can adversely affect calcium balance and mineralization of calcium-dependent tissues. The binding of the medication to calcium may also lead to growth retardation and pigmented teeth. Furthermore, tetracycline increases urinary calcium excretion. Thus, with prolonged use, tetracyclines contribute to calcium depletion and can adversely effect bone formation.

Research

Most of the findings leading to statements about this interaction involve calcium-based antacids and calcium-rich foods, but they are still reasonably applicable to calcium supplements. In a review of the effect of polyvalent metallic cations on absorption of tetracyclines, Neuvonen ¹⁹⁸ noted that serum concentrations of these antibiotics generally remain within the therapeutic range. Nevertheless, he concluded that “the pharmacokinetic interactions in absorption of tetracyclines likely to be clinically significant in cases where the infecting pathogens are moderately resistant to tetracyclines and relatively high serum concentrations are needed for proper bacteriostasis.” In a clinical trial (crossover design) involving 12 healthy volunteers, Jung et al. ²⁰⁰ observed that even a small volume of milk containing extremely small amounts of calcium can severely impair the absorption, and subsequent bioavailability, of tetracycline.

Long-term use of tetracycline antibiotics is highly likely to produce adverse effects on calcium and related tissues and developmental processes. Tetracyclines form a stable calcium complex in any bone-forming tissue. In particular, the interaction between tetracycline and calcium-rich foods (e.g., milk products) exerts adverse effects on bone and teeth that are well documented and widely recognized. ^201,202 Unwanted pigmentation and other problems with tooth development caused by tetracycline are well known to dentists and the general public. The tetracyclines also tend to localize in tumors, necrotic or ischemic tissue, liver, and spleen and form tetracycline-calcium orthophosphate complexes at sites of new bone formation.

Tetracyclines are potent inhibitors of osteoclast function (i.e., antiresorptive). Vernillo and Rifkin ²⁰³ describe the processes by which tetracyclines can affect several parameters of osteoclast function and consequently inhibit bone resorption: (1) altering intracellular calcium concentration and interacting with the putative calcium receptor; (2) decreasing ruffled border area; (3) diminishing acid production; (4) diminishing the secretion of lysosomal cysteine proteinases (cathepsins); (5) inducing cell retraction by affecting podosomes; (6) inhibiting osteoclast gelatinase activity; (7) selectively inhibiting osteoclast ontogeny or development; and (8) inducing apoptosis, or programmed cell death, of osteoclasts. For example, a decrease in the fibula growth rate has been observed in premature infants receiving oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. ²⁰⁴

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The mutual impairment of absorption characterizing the interaction between tetracyclines and calcium absorption is highly probable, usually clinically significant, and easily avoided through careful management and instruction. This effect on bone formation carries a significantly greater risk when growth and bone formation is most active, such as with infants and children. Avoiding this interaction is also particularly important in adolescents (e.g., being treated for acne) in the midst of the life stage where they need to attain maximum bone density.

Calcium in the form of antacids, milk products, and supplements should be avoided while using tetracycline-class antibiotics. When continued use of calcium supplements is deemed appropriate and necessary, the calcium supplement (as well as calcium-rich foods) should be taken at least 3 hours apart from ingestion of the medication. Properly managed, separation allows continued effective use of both calcium and the tetracycline antibiotic.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Bimodal or Variable Interaction, with Professional Management
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Effect and Mechanism of Action

Thiazide diuretics increase calcium retention by decreasing urinary calcium excretion through their effects on the cortical-diluting segment of the nephron, most likely from the peritubular side. ^205-207 Decreased intestinal calcium absorption, suppressed PTH secretion, and inhibited vitamin D synthesis can also result as secondary compensations. Increased renal reabsorption of calcium induced by thiazide diuretics may increase the risk of developing hypercalcemia (and possibly metabolic alkalosis) as a result of concomitant administration of calcium supplements (and/or vitamin D).

Research

Consistent evidence indicates that thiazide-induced decrease in urinary calcium excretion can alter numerous parameters of calcium and vitamin D metabolism and increase risk of transient hypercalcemia, but research has not extended to investigation of potential long-term implications. Leppla et al. ²⁰⁸ conducted a small clinical trial involving seven patients with renal stones to investigate the potential therapeutic role of amiloride in calcium nephrolithiasis. They observed that two doses of amiloride (2.5 mg/day) reduced urinary calcium in two subjects with kidney stones. This decrease in urinary calcium was enhanced in five subjects when amiloride was coadministered with two doses of hydrochlorothiazide (25 mg/day). In a 6-month clinical trial involving six postmenopausal women with osteoporosis, Sakhaee et al. ²⁰⁹ demonstrated that coadministration of hydrochlorothiazide (50 mg/day) and vitamin D (50 µg/day) reduced urinary calcium excretion by 22% but also decreased gastrointestinal calcium absorption by 25%. Riis and Christiansen ²⁰⁶ studied the actions of bendroflumethiazide (5 mg/day), along with 500 mg/day calcium, on vitamin D metabolism in a 12-month placebo-controlled clinical trial in 19 healthy early-postmenopausal women. Subjects in the thiazide group demonstrated a significant elevation in the serum concentration of 24,25-dihydroxycholecalciferol and a tendency toward decreased serum 1,25-dihydroxycholecalciferol, although mean serum 25-hydroxycholecalciferol remained unchanged. The authors noted that all biochemical indices of calcium metabolism were unchanged in the thiazide group, except for a highly significant decrease in urinary calcium.

Some researchers and clinicians have proposed exploiting this interaction between thiazide diuretics and calcium as a potential therapeutic tool in reducing bone loss and preventing osteoporotic fractures. In a 1998 review article, Rejnmark et al. ²¹⁰ reported that thiazide use is associated with higher BMD, reduced age-related bone loss, and a reduced risk of hip fractures and attributed it not only to decreased calcium excretion, but also possibly to a decrease in PTH-stimulated bone resorption and an associated reduction in the bone turnover rate. However, prudence suggests that such beneficial “side effects” do not provide adequate justification for prescribing this class of medications solely for that purpose, given the other risks associated with their use and the lack of evidence supporting efficacy. Furthermore, the most relevant evidence indicates that any beneficial effect on calcium in bone metabolism is transient. Thus, in the Rotterdam Study, a prospective population-based cohort study involving 7891 individuals 55 years of age and older, Schoofs et al. ²¹¹ reported 281 hip fractures and observed that current use of thiazides for more than 1 year was statistically significantly associated with a lower risk for hip fracture (with no clear dose dependency) compared with nonuse. However, this lower risk disappeared approximately 4 months after thiazide use was discontinued.

Reports

Concomitant use of thiazide diuretics and calcium supplements has been associated with numerous case reports describing hypercalcemia, as well as signs and symptoms of the milk-alkali syndrome, including dizziness, weakness, hypercalcemia, and metabolic alkalosis with respiratory compensation. ^212-214 For example, Crowe et al. ²¹⁵ described a case of symptomatic and reversible hypercalcemia in a 78-year-old female patient taking a combination diuretic (hydrochlorothiazide and amiloride) along with six to eight antacid tablets daily (each containing 680 mg calcium carbonate and 80 mg magnesium carbonate) for several years. Constipation, dehydration, and hypercalcemic alkalosis all resolved when the medications were discontinued during hospitalization. Gora et al. ²¹⁶ published the case report of a 47-year-old man who was diagnosed with milk-alkali syndrome after being hospitalized with elevated serum calcium (6.8 mEq/L) and serum creatinine (7.2 mg/dL) as well as metabolic alkalosis. During the preceding 2 years he had been self-medicating for dyspepsia with 15 to 20 calcium carbonate tablets daily, each containing 500 mg, while also taking chlorothiazide. His condition improved shortly after this regimen was discontinued.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing thiazide diuretics for treatment of hypertension frequently need to treat such patients concurrently for osteoporosis. In such situations, oral calcium supplements in common dosages do not usually influence blood calcium levels significantly and rarely would impact levels enough to cause clinically significant hypercalciuria.

Thiazides should not be used as a substitute for calcium (and vitamin D) supplementation in the prevention of bone loss and treatment of osteoporosis. Although individuals on long-term thiazide therapy could theoretically reduce calcium intake during such therapy, the available evidence indicates that such beneficial effects do not continue after the thiazide has been discontinued. Evidence is lacking and further research warranted to determine whether any rebound effects on calcium balance or bone loss occurs after thiazide use is suspended, as occurs with some medications.

Given the uncertain implications of the available evidence, physicians are advised to closely supervise and regularly monitor calcium levels when prescribing thiazide diuretics, particularly before initiating or increasing any vitamin D supplementation, and to instruct patients to watch for symptoms of hypercalcemia. In some cases, calcium intake may need to be reduced. When thiazides are indicated, supplementation with potassium and magnesium is usually appropriate to compensate for drug-induced nutrient depletion.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Bimodal or Variable Interaction, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Effect and Mechanism of Action

Enhanced renal vasoconstriction and renal tubular sodium reabsorption are calcium-dependent functions mediated by noradrenaline and angiotensin II (Ang II) that have been implicated in the pathogenesis of essential hypertension. Calcium supplements (especially in conjunction with high doses of vitamin D) may interfere with the hypotensive activity of and reduce the therapeutic response to verapamil and related calcium channel blockers by increasing calcium availability. Even though the primary activity of these medications involves calcium antagonism, the mechanism of these antagonistic effects on calcium has not yet been fully established. Felodipine use has been associated with increased calcium excretion, and calcium channel blockers may theoretically contribute to increased bone loss. Verapamil may decrease endogenous production of vitamin D and induce target-organ PTH resistance. Nevertheless, calcium administration may reduce adverse effects of calcium channel blockers, and concurrent use of verapamil and intravenous (IV) calcium salts, in particular, can be therapeutically efficacious.

Research

It has been reported that calcium salts may reverse the clinical effects and toxicities associated with verapamil. ²¹⁷ Weiss et al. ²¹⁸ found that calcium gluconate, when given as a pretreatment infusion, prevented the fall in blood pressure induced by verapamil, and when administered after verapamil, it restored blood pressure to control values. These researchers also noted that administration of calcium did not alter the antiarrhythmic effect of verapamil. Similarly, in a clinical trial conducted by Haft and Habbab, ²¹⁹ pretreatment with IV calcium chloride in patients with supraventricular arrhythmias reduced the incidence of hypotensive side effects without compromising the antiarrhythmic effect of verapamil.

Calcium absorption depends on, and calcium function is intertwined with, vitamin D activity. In a 1982 in vitro study, Lerner and Gustafson ²²⁰ reported that verapamil inhibited 1α(OH) ² D ³ -stimulated bone resorption in tissue culture. In an animal model using rats fed a high-calcium diet, Fox and Della-Santina ²²¹ found that chronic oral verapamil administration decreased 1,25(OH) ² D ³ levels (by reducing production) and increased plasma immunoreactive PTH (most likely by inducing target-organ PTH resistance). In contrast, verapamil produced no significant effect on 1,25(OH) ² D ³ levels in rats fed a low-calcium diet. A study by Hulthen and Katzman ²²² involving 10 patients with essential hypertension found that felodipine use was associated with increased calcium excretion.

Reports

In an isolated report, Bar-Or and Gasiel ²²³ described a case in which calcium adipate and calciferol antagonized the heart rate–limiting effect of verapamil in a patient being treated for atrial fibrillation.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing verapamil or other calcium channel blockers are advised to exercise caution regarding the concomitant use of calcium (and vitamin D). Concurrent calcium administration in individuals undergoing treatment with calcium channel blockers may be problematic or beneficial, depending on the condition for which the drug has been prescribed, the dosage of calcium intake, and the characteristics of the individual patient being treated. Although of low probability, the potential for an adverse interaction can present strategic concerns because many patients treated with verapamil may also have or be at risk for osteoporosis, such that calcium and vitamin D support is an important concomitant need.

Patient self-administration of calcium should be avoided during treatment with a calcium channel blocker. However, some physicians routinely prescribe very low dosages of calcium, often in the range of 25 to 30 mg per day, for patients who have been diagnosed with angina pectoris or cardiac arrhythmias, but who have no history of hypertension, as a means of reducing excessive and unnecessary blood pressure–lowering activity by the medication. Close supervision and regular monitoring, preferably within the context of integrative care involving health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics, are essential in cases in which concurrent use of verapamil (or a related calcium channel blocker) and calcium (especially with vitamin D) is clinically appropriate. In particular, regular monitoring of blood pressure is required during any coadministration, especially before initiating or significantly changing the level of calcium intake. In cases of overdose with verapamil or other calcium channel blockers, IV calcium chloride or gluconate is the treatment of choice.

Intramuscular (IM), intravenous (IV), and subcutaneous (SC) forms: Albuterol/salbutamol, rimiterol (Pulmadil).

Extrapolated: IM, IV, and SC forms: Fenoterol (Berotec), isoetharine (Arm-A-Med, Bronkosol, Bronkometer), pirbuterol (Exirel), salmeterol, tulobuterol (Brelomax).

Similar properties but evidence indicating no or reduced interaction effects: Inhalation forms: Albuterol (salbutamol; Albuterol Inhaled, Proventil, Ventolin); combination drug: albuterol and ipratropium bromide (Combivent); isoproterenol (isoprenaline; Isuprel, Medihaler-Iso), levalbuterol (Xopenex), metaproterenol (Alupent), salmeterol (Serevent, combination drug: Advair), terbutaline (Brethaire, Brethine, Bricanyl).

Intravenous administration of salbutamol (albuterol) and rimiterol in therapeutic doses produced dose-related decreases in plasma levels of calcium, as well as magnesium, phosphate, and potassium, in four subjects. ²²⁴ These researchers advised caution in patients with abnormal glucose tolerance, potassium depletion, or predisposition to lactic acidosis and suggested rimiterol as preferable for infusion because of its short plasma half-life. Further research is warranted to determine if these beta-2-adrenoceptor agonists can induce such adverse effects to a clinically significant degree in individuals being treated for asthma and related conditions over an extended period.

Beclomethasone (Beclovent; Beconase; Beconase AQ; QVAR; Vancenase; Vancenase AQ; Vanceril).

Similar properties but evidence indicating no or reduced interaction effects: Other inhaled corticosteroids.

Adverse effects of inhaled corticosteroids are generally presumed to be significantly less than those from oral corticosteroids. However, investigators have reported that most of the beclomethasone from a metered-dose inhaler (MDI) is actually swallowed and can impair calcium absorption. In a 2-week randomized, double-blind, placebo-controlled, crossover trial involving 12 healthy subjects, Smith et al. ¹²¹ found that during the period in which they received oral doses of beclomethasone dipropionate (500-µg capsules twice daily), subjects demonstrated a 12% reduction in calcium absorption (measured by strontium absorption test) and a 23% reduction in 24-hour urinary cortisol excretion during the same week. These researchers concluded that decreased calcium absorption resulting from swallowed corticosteroids may contribute to adverse effects of inhaled steroids. Well-designed clinical trials of longer duration are warranted to investigate whether such effects may be a causative factor in long-term bone loss, and whether calcium supplementation or dietary calcium enrichment might be indicated. ^225-228

See also Corticosteroids, Oral.

Caffeine (Cafcit, Caffedrine, Enerjets, NoDoz, Quick Pep, Snap Back, Stay Alert, Vivarin).

Combination drugs: Acetylsalicylic acid and caffeine (Anacin); acetylsalicylic acid, caffeine, and propoxyphene (Darvon Compound); ASA and carisoprodol (Soma Compound); acetylsalicylic acid, codeine, butalbital, and caffeine (Fiorinal); acetominophen, coffee (Caffea arabica, Caffea canephora, Caffea robusta),butalbital, and caffeine (Fioricet).

Caffeine is found in coffee, tea, soft drinks, chocolate, guaraná (Paullinia cupana),nonprescription over-the-counter (OTC) medications, and supplements containing caffeine or guaraná. For decades, caffeine in general and coffee in particular have been suspected of depleting calcium and contributing to bone loss. Although early studies suggested an epidemiological basis for this conclusion, the evolving picture from continued research has downsized the scope of clinical significance and clarified factors of susceptibility. Caffeine can lead to a small negative calcium balance because of a weak interference with calcium absorption efficiency, particularly in individuals with inadequate calcium intakes. ²²⁹ Caffeine can also induce a significant acute calcium diuresis, ^224,230 but this renal effect is biphasic ²³¹ ; that is, an acute increase in calcium diuresis is followed by a fall in urinary calcium. Two human trials have found that coffee intake, rather than caffeine, was associated with a negative balance shift of 4 to 6 mg calcium daily for each 100 ml coffee consumed. Conversely, but consistent with the overall pattern, one observational study found accelerated bone loss in 205 healthy postmenopausal women who drank two to three cups of coffee daily and consumed less than 800 mg of calcium daily. Further research is warranted to determine the effects of caffeine in populations characterized by different levels and sources of calcium intake, gender, life stage, bone density, and other potentially influential factors and to compare the variable effects of different sources of caffeine, as well as decaffeinated coffee and differing methods of preparation.

Cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ).

Cisplatin is nephrotoxic and may cause kidney damage, resulting in depletion of calcium, magnesium, potassium, and phosphate. Calcium supplementation may be appropriate but must be approached with caution and close monitoring, especially in patients with compromised renal function. Strategic integrative protocols, adapted to the particular characteristics and needs of the individual patient, offer expanded possibilities for enhanced care and improved outcomes within the context of collaborative care involving health care professionals trained and experienced in both conventional oncology and nutritional therapeutics.

Colchicine

An isolated case report published by Frayha et al. ²³² describes acute colchicine poisoning resulting in symptomatic hypocalcemia in a young female with periodic polyserositis. Experimental data suggest that colchicine-induced hypocalcemia is secondary to colchicine inhibition of bone resorption. Findings from research using a rat model indicate that hypocalcemia may be mediated by interference with the regulatory mechanisms of bone cell calcium homeostasis, and that the destruction of microtubules may be closely related to the development of the hypocalcemia. ²³³

Further research may be warranted to determine whether long-term colchicine therapy might contribute to bone loss or other calcium depletion effects, what circumstances or patient characteristics influence susceptibility to a clinically significant interaction, and what nutritional countermeasures might be safe and effective.

Cycloserine (Seromycin).

Cycloserine may interfere with absorption of calcium and other nutrients, particularly minerals. ^234,235 The clinical significance and therapeutic implications of this potential interaction are as yet not understood.

Diclofenac potassium (Cataflam), diclofenac sodium (Voltaren).

Related COX-1 inhibitors:Diclofenac combination drug: diclofenac and misoprostol (Arthrotec); diflunisal (Dolobid), etodolac (Lodine), fenoprofen (Dalfon), furbiprofen (Ansaid), ibuprofen (Advil, Excedrin IB, Motrin, Motrin IB, Nuprin, Pedia Care Fever Drops, Provel, Rufen); combination drug: hydrocodone and ibuprofen (Reprexain, Vicoprofen); indomethacin (indometacin; Indocin, Indocin-SR), ketoprofen (Orudis, Oruvail), ketorolac (Acular ophthalmic, Toradol), meclofenamate (Meclomen), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), naproxen (Anaprox, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene), salsalate (salicylic acid; Amigesic, Disalcid, Marthritic, Mono Gesic, Salflex, Salsitab), sulindac (Clinoril), tolmetin (Tolectin).

COX-2 inhibitor:Celecoxib (Celebrex).

See also Indomethacin.

Diclofenac can decrease the amount of urinary calcium excretion ²³⁶ ; it may also inhibit bone resorption in postmenopausal women. ⁶² Thus, theoretically, coadministration could prevent bone loss in postmenopausal women. Further research is warranted.

Also, in a controlled clinical trial, Miceli-Richard et al. ²³⁷ demonstrated that acetaminophen (4 g/day) was not effective in treatment of symptomatic osteoarthritis of the knee.

Digoxin (Digitek, Lanoxin, Lanoxicaps, purgoxin).

Deslanoside (cedilanin-D), digitoxin (Cystodigin), ouabain (g-strophanthin).

Calcium may interact with digoxin and related agents in two distinct ways. First, the two substances can interact in an additive or possibly synergistic manner. The inotropic action of cardiac glycosides appears to be associated, at least in part, with increased intracellular calcium availability. Chronotropic effects are also mediated by calcium. Thus, high calcium intake (especially by parenteral administration) can produce small increases in plasma calcium, thereby increasing the activity of digoxin and elevating the risk of arrhythmias and other aspects of digoxin toxicity. Second, digoxin also increases renal clearance and could lead to calcium depletion; hypocalcemia can negate the therapeutic activity of digoxin.

Evidence from clinical trials involving digoxin in human subjects, especially cardiac patients, is limited for obvious reasons given the high risk associated with any such experiments. In a 1965 paper, Kupfer and Kosovsky ²³⁸ reported that cardiac glycosides can interfere with calcium reabsorption and increase calcium excretion in a dog model through their effect on renal tubular transport of calcium. Although often cited, the clinical significance of this finding has never been established. Sonnenblick et al. ²³⁹ compared serum digoxin, calcium, potassium, and magnesium concentrations and arterial pH in 18 patients with gastrointestinal (GI) manifestations of digoxin toxicity with 19 patients with digoxin-induced cardiotoxicity, specifically automaticity. Patients with digoxin-induced GI symptoms had high serum concentrations of the drug. In contrast, those with drug-induced cardiotoxicity (automaticity) had therapeutic concentrations of digoxin but demonstrated higher calcium/potassium ratios and higher pH values.

The concern regarding this interaction dates back to a journal article published more than 70 years ago. In 1936, Bower and Mengle ²⁴⁰ published a “warning” in JAMAregarding two fatalities attributed to the “additive effects of calcium and digitalis.” Although plausible and frequently cited for decades, no causal relationship was firmly established in these incidents. Techniques for laboratory assessment of digoxin serum levels were unavailable at that time, so it is more likely that the patients had digoxin toxicity and coincidentally were taking calcium. Other case reports describe cardiac arrhythmias associated with concomitant administration of cardiac glycosides and calcium preparations, primarily involving IV administration. ²⁴¹

In consideration of the drug's narrow therapeutic range, physicians prescribing digoxin and related cardioactive agents should advise patients to maintain stable calcium intake. Prudence suggests that blood calcium levels be monitored closely when significant or rapid changes in calcium status or intake are anticipated or undertaken. Calcium supplementation may be appropriate if deficiency is indicated, but any change in intake should be gradual and supervised closely. In most cases, checking serum calcium at onset of digoxin therapy is probably adequate. After that, monitoring digoxin level is probably the most important test. Hypocalcemia or hypercalcemia can clearly be problematic with digoxin therapy but generally is not caused by calcium supplements or their absence.

Although calcium status plays a significant role in the efficacy and safety of digoxin, supplemental or dietary calcium intake is unlikely to interact with digoxin to a clinically significant degree in most cases. Hypercalcemia increases digoxin toxicity, and hypocalcemia reduces digoxin's therapeutic effect. However, oral calcium supplements in common dosages do not usually influence blood levels of calcium levels to a significant degree and rarely would impact blood levels of calcium enough to cause a clinically significant interaction with digoxin. In absence of calcium deficiency, mimimal calcium is absorbed from the gut. In a deficiency state, calcium is mobilized from bone, through increased parathyroid hormone (PTH) secretion, to maintain the blood levels. Thus, under normal conditions, calcium homeostasis regulates blood calcium levels within a range unlikely to destabilize a patient taking digoxin.

Ionized calcium, normally tightly regulated by vitamin D, calcitonin, and PTH, would much more likely be problematic than calcium intake. Intravenous calcium carries a significant risk for an adverse interaction. Physicians administering parenteral or IV calcium to individuals undergoing digoxin therapy will presumably be closely monitoring such patients and working within a setting suitable to providing the necessary responses to unstable situations or unexpected developments. Low potassium and magnesium also increase digoxin toxicity.

Dobutamine (Dobutrex).

Human research indicates that IV administration of calcium chloride may diminish the therapeutic effect of dobutamine, specifically its cardiac-stimulating properties.

In a clinical trial involving 22 patients administered dobutamine after coronary bypass surgery, Butterworth et al. ²⁴² observed a 30% reduction in cardiac output with concomitant administration of calcium chloride by continuous infusion. These subjects had a normal cardiac output before calcium administration. In contrast, milrinone was not affected by the calcium administration. The authors could not demonstrate the mechanism involved in this interaction but suggested that calcium may interfere with signal transduction through the beta-adrenergic receptor complex.

Physicians administering dobutamine are advised to monitor for decreased cardiac output or other reduction of therapeutic effects if exogenous calcium is administered or the dose increased, especially intravenously. Evidence is lacking to support any extrapolation of this finding to oral calcium supplementation.

Azithromycin (Zithromax), clarithromycin (Biaxin), dirithromycin (Dynabac), erythromycin, oral (EES, EryPed, Ery-Tab, PCE Dispertab, Pediazole), troleandomycin (Tao).

Erythromycin may interfere with the absorption and activity of calcium and other nutrients. Although not usually clinically significant with short-term administration, the increased risk of calcium depletion can become a concern with extended use. Further research is warranted to investigate potential adverse effects on calcium balance and bone metabolism with extended macrolide therapy.

Physicians prescribing erythromycin and related macrolide antibiotics internally for longer than 2 weeks are advised to supplement calcium (as well as folic acid, vitamins B ⁶ and B ² , and magnesium) as a preventive measure, with separation of oral intake. Any potential drug-induced adverse effect on bone formation would carry a significantly greater risk when growth and bone formation are most active, such as with infants and children. Avoiding such an interaction would also be particularly important in adolescents (e.g., being treated for acne) in the midst of the life stage where they need to attain maximum bone density.

Hydroxychloroquine (Plaquenil).

Related: Chloroquine (Aralen, Aralen HCl).

Preliminary data suggest that hydroxychloroquine might induce hypocalcemia or calcium depletion. An isolated case report described the use of hydroxychloroquine to block the formation of active vitamin D and normalize elevated blood levels of calcium in a 45-year-old woman with sarcoidosis. ²⁴³ Evidence is lacking to confirm or disprove such effects of hydroxychloroquine administration in individuals not presenting with sarcoidosis or elevated calcium. Pending further research with well-designed clinical trials, physicians prescribing hydroxychloroquine are advised to monitor vitamin 25(OH)D and calcium status.

Indapamide (Lozol).

As a thiazide-like diuretic, indapamide carries a high probability of interacting with nutrients in a manner similar to interactions observed with thiazide diuretics. Thus, preliminary data suggest that indapamide may cause slight elevation in blood calcium levels, and that concomitant administration of calcium supplements could potentially aggravate this risk. ^244-247 Physicians prescribing indapamide should monitor blood calcium levels and consider whether calcium supplementation is contraindicated for the individual being treated.

Indomethacin (Indometacin; Indocin, Indocin-SR).

Prostaglandins E ¹ and E ² (PGE ² ) stimulate bone resorption. This has been proposed as a possible mechanism for hypercalcemia in malignancy (particularly renal cell carcinoma). Some in vitro and in vivo research has shown that indomethacin, a specific prostaglandin biosynthesis inhibitor, may reduce plasma calcium (and phosphate) levels. However, in a trial involving patients with breast cancer, Coombes et al. ²⁴⁸ found that indomethacin did not reduce serum calcium levels in patients with hypercalcemia, nor did it reduce skeletal destruction, as measured by the urinary hydroxyproline/creatinine ratio and urinary calcium in normocalcemic or hypercalcemic patients with osteolytic metastases. Similarly, in a study of PGE ² , parathormone (PTH), and response to indomethacin in patients with hypercalcemia of malignancy, Brenner et al. ²⁴⁹ found that PGE ² and calcium fell to normal levels in 3 of 14 patients (breast, colon, renal carcinomas) after administration of indomethacin. In a rat model, Gomaa et al. ²⁵⁰ observed that indomethacin increased serum levels of calcium.

This potential interaction could be especially relevant in patients using indomethacin for joint pain and inflammation (e.g., osteoarthritis) or after orthopedic procedures. However, evidence is lacking to determine whether coadministration of nutrients might be appropriate or beneficial.

Laxatives, Stimulant

Stimulant laxatives may reduce absorption of calcium from dietary or supplemental sources. ²⁵¹ With prolonged use, this action could result in adverse effects. Physicians are generally advised to inform patients to limit the duration of stimulant laxatives for many reasons, including potential for decreased absorption and potential depletion of key nutrients, including calcium.

Bumetanide (Bumex), ethacrynic acid (Edecrin), furosemide (Lasix), torsemide (Demadex).

Loop diuretics act in the luminal side of the ascending part of the kidney's diluting segment and will increase the urinary excretion of calcium, subsequently increasing blood calcium levels. ²⁵² This action could theoretically induce osteopenia; it may also increase the risk of calcium oxalate stones.

The available data from clinical research suggest that loop diuretics can alter calcium levels but are inadequate for determining whether and under what conditions such interaction may be clinically significant. In a trial involving 16 healthy volunteers treated with bumetanide, Davies et al. ²⁵³ found that the effects on calcium may be relatively less pronounced with this medication than with other drugs in this class; urinary calcium loss was initially elevated but was followed by retention at 24 hours (0.25-1.0 mg orally). Ogawa et al. ²⁵⁴ observed that furosemide (40 mg) caused marked calciuresis but also elevated serum calcium levels in an experiment involving five healthy male subjects. The authors noted that the effects of increased calcium excretion “may not extend to bone calcium remodeling at least in such a short-term experiment.”

Fujita et al. ²⁵⁵ examined the effects of short-term administration of furosemide (4-7 days) on the response to exogenous parathyroid extract in six normal subjects. All six subjects demonstrated marked increases in urinary calcium excretion, reduced serum ionized calcium levels, and significant increase in urinary cyclic adenosine monophosphate (cAMP) from the control to the furosemide periods. Further research with well-designed clinical trials is warranted to clarify the clinical effects of loop diuretics on calcium metabolism and homeostasis and to determine guidelines for a safe, effective clinical response.

Physicians prescribing loop diuretics should advise patients to discuss their status, and/or consult with a health care professional trained and experienced in nutritional therapies, before initiating or increasing their level of calcium supplementation. Despite a lack of evidence establishing a general need for calcium support, increased calcium intake through diet or supplements may be appropriate during loop diuretic therapy in some individuals at high risk for bone loss. However, in patients taking both loop diuretics (especially furosemide) and calcium supplementation, testing of 24-hour urinary calcium levels may be prudent in patients with increased risk of calcium oxalate stones. Choosing which form of calcium to use may be significant in supporting bone density while minimizing risk of nephrolithiasis.

Conjugated equine estrogens and medroxyprogesterone (Premelle cycle 5, Prempro); medroxyprogesterone, injection (Depo-Provera, Depo-subQ Provera 104); medroxyprogesterone, oral (Cycrin, Provera).

The evidence is mixed and preliminary, but the available data indicate that medroxyprogesterone administration probably increases bone loss, even with calcium coadministration. Hergenroeder et al. ²⁵⁶ conducted a randomized, controlled clinical trial involving 24 Caucasian women, age 14 to 28, with hypothalamic amenorrhea or oligomenorrhea, comparing the effects of treatment using oral contraceptives (OCs), medroxyprogesterone, or placebo over 12 months. Measuring bone mass at 6 and 12 months, they found that spine and total-body bone mineral measurements in amenorrheic subjects at 12 months were greater in the OC group than in the medroxyprogesterone and placebo groups, and that no detectable improvement in bone mineral associated with medroxyprogesterone use in oligomenorrheic subjects. There were no measurable differences in hip bone mineral calcium and bone mineral density (BMD) measurements at 12 months among the three groups. Merki-Feld et al. ²⁵⁷ conducted a 2-year prospective study on the effects of depot medroxyprogesterone acetate (DMPA) on bone mass response to estrogen and calcium therapy in women age 30 to 45. In particular, their investigation focused on the effects of estrogen or calcium substitution during the second year of follow-up in seven DMPA users with a high annual bone loss during the first year. The baseline cortical and trabecular bone mass (TBM) and the annual change was no different in DMPA users and controls. Over 24 months the researchers measured an increase in TBM of 0.6% and a decrease in cortical bone mass of 0.1% in exposed women. Some (but not all) DMPA users with bone loss during the first year could be successfully treated with estradiol or calcium. These authors concluded that no significantly accelerated bone loss was associated with DMPA use in women 30 to 45 years of age.

Berenson et al. ²⁵⁸ compared the effects of 24 months of DMPA on lumbar spine BMD compared with self-selected oral contraconception (pills) and nonhormonal contraception (controls) in 191 women age 18 to 33. They observed that women using DMPA for 24 months demonstrated on average a 5.7% loss in BMD, with a 3.2% loss occurring between months 12 and 24. In contrast, users of desogestrel pills experienced an average 2.6% loss in BMD after 24 months. These authors concluded that DMPA appeared to be associated with linear pattern of decreased BMD during the first 2 years of use.

Calcium nutriture and weight-bearing exercise form the foundation of bone health in women during the menstrual years. Physicians prescribing medroxyprogesterone will want to remind patients of the basic preventive needs and suggest that consistency may be especially important given the potential for increased bone loss under the influence of this form of contraceptive.

Mineral Oil (Agoral, Kondremul Plain, Milkinol, Neo-Cultol, Petrogalar Plain).

Mineral oil, as a lipid solvent, may absorb many substances and interfere with normal absorption of calcium and other nutrients. ²⁵⁹ The effect of mineral oil on fat-soluble nutrients such as vitamin D, which is essential to calcium absorption, can further adversely influence calcium bioavailability. Although some research suggests that these interactions may be clinically significant, especially with long-term administration and simultaneous intake, the collective evidence is mixed and inconclusive.

Health care professionals advising patients using mineral oil for any extended time can recommend regular use of a multivitamin-mineral supplement as potentially beneficial. Administering mineral oil on an empty stomach or ingesting vitamin/mineral supplements at least 2 hours before or after the mineral oil can effectively minimize malabsorption of fat-soluble nutrients. However, in general, the internal use of mineral oil should be limited to less than 1 week.

Amiloride (Midamor), spironolactone (Aldactone), triamterene (Dyrenium); combination drugs: amiloride and hydrochlorothiazide (Moduretic); spironolactone and hydrochlorothiazide (Aldactazide); triamterene and hydrochlorothiazide (Dyazide, Maxzide).

Potassium-sparing diuretics can increase calcium loss through urinary excretion, but evidence is lacking to determine whether and under what circumstances this effect might lead to a clinically significant pattern of calcium depletion. ^260-262 Reduced calcium loss has also been posited, similar to that found with thiazide diuretics.

Leppla et al. ²⁰⁸ conducted a small clinical trial involving seven patients with renal stones to investigate the potential therapeutic role of amiloride in calcium nephrolithiasis. They observed that two doses of amiloride (2.5 mg/day) reduced urinary calcium in two subjects with kidney stones. This decrease in urinary calcium was enhanced in five subjects when amiloride was coadministered with two doses of hydrochlorothiazide (25 mg/day). The clinical implications of this observed effect on calcium metabolism are unclear at this time.

Triamterene may increase urinary calcium excretion. However, the clinical implications of this possible interaction are limited.

The evidence regarding this interaction is inconsistent and has yet to mature. Nevertheless, physicians prescribing potassium-sparing diuretics are advised to be aware of potential alterations in calcium status caused by these agents and to consider calcium supplementation or contraindication, as indicated by the individual patient's age, gender, medical history, BMD, and other relevant factors.

Acitretin (Soriatane), bexarotene (Targretin), etretinate (Tegison), isotretinoin (13- cisretinoic acid; Accutane), tretinoin (All-Trans-Retinoic Acid, ATRA, Atragen, Avita, Renova, Retin-A, Vesanoid, Vitinoin).

Long-term or high-dose administration of vitamin A derivatives (retinoids) may produce a variety of skeletal adverse effects in humans. Kindmark et al. ²⁶³ investigated the early effects of oral isotretinoin therapy on bone turnover and calcium homeostasis in 11 consecutive patients with nodulocystic acne. They reported that markers of bone turnover and urine levels of calcium and hydroxyproline decreased significantly within 5 days of treatment. There was also a statistically significant decrease in serum calcium, with a minimum on day 5, and a marked increase in serum PTH. However, with continued treatment, the abnormal levels of these markers returned to baseline values within 14 days. Further research with well-designed clinical trials is warranted to investigate long-term implications of retinoic acid therapy on calcium economy and bone health.

Physicians prescribing retinoic acid or related retinoid therapies internally for longer than 2 weeks are advised to supplement calcium (300 mg three times daily) as a preventive measure.

Acetylsalicylic acid (acetosal, acetyl salicylic acid, ASA, salicylsalicylic acid; Arthritis Foundation Pain Reliever, Ascriptin, Aspergum, Asprimox, Bayer Aspirin, Bayer Buffered Aspirin, Bayer Low Adult Strength, Bufferin, Buffex, Cama Arthritis Pain Reliever, Easprin, Ecotrin, Ecotrin Low Adult Strength, Empirin, Extra Strength Adprin-B, Extra Strength Bayer Enteric 500 Aspirin, Extra Strength Bayer Plus, Halfprin 81, Heartline, Regular Strength Bayer Enteric 500 Aspirin, St. Joseph Adult Chewable Aspirin, ZORprin); combination drugs: ASA and caffeine (Anacin); ASA, caffeine, and propoxyphene (Darvon Compound); ASA and carisoprodol (Soma Compound); ASA, codeine, and carisoprodol (Soma Compound with Codeine); ASA and codeine (Empirin with Codeine); ASA, codeine, butalbital, and caffeine (Fiorinal); ASA and extended-release dipyridamole (Aggrenox, Asasantin).

Salsalate (salicylic acid; Amigesic, Disalcid, Marthritic, Mono Gesic, Salflex, Salsitab).

Experimental data indicate that salicylic acid analogs with the carboxyl group adjacent to the hydroxyl group on the benzene ring can induce hypocalcemia. Kato et al. ²⁶⁴ found that orally administered aspirin and sodium salt of o-hydroxybenzoic acid (Na-salicylate), but not the sodium salt of m- and p-hydroxybenzoic acid (HBA), induced hypocalcemia; 2,5-dihydroxybenzoic acid (DHBA) and PAS sodium dihydrate (PAS-Na) caused hypocalcemia when administered intravenously but not orally. Related findings from IV injection of aspirin–dl-lysine (water-soluble aspirin) and SA–dl-lysine suggest that prostaglandins are not involved in the process of aspirin-induced hypocalcemia in the rat. ²⁶⁴

Further research involving well-designed clinical trials is warranted to assess the short-term effects and long-term clinical implications of this potential interaction between salicylates and calcium, particularly in regard to long-term bone loss, joint pain, osteoarthritis, and analgesic use.

Sodium fluoride (Fluorigard, Fluorinse, Fluoritab, Fluorodex, Flura-Drops, Flura-Tab, Karidium, Luride, Pediaflor, PreviDent).

Calcium may reduce absorption of fluoride, and vice versa, when taken simultaneously. ²⁶⁵

In a review article, Deal ²⁶⁶ reported that fluoride monotherapy can transfer calcium from leg bones to the spine, thus increasing the risk of stress fractures. However, coadministration of 1500 mg calcium daily and slow-release forms of fluoride increases the lumbar spine BMD without causing fractures.

Haguenauer et al. ²⁶⁷ conducted a meta-analysis of randomized controlled trials investigating efficacy of fluoride therapy on bone loss, vertebral and nonvertebral fractures, and adverse effects in postmenopausal women. Although fluoride therapy demonstrates an ability to increase lumbar spine BMD, it does not result in a reduction in vertebral fractures. Further, increasing fluoride dose raises the risk of nonvertebral fractures and incidence of GI adverse effects without providing any beneficial effect on the vertebral fracture rate. Health care professionals experienced in nutritional therapies report that sodium fluoride, when used as a treatment for osteoporosis, does harden bone, but it also renders bone less elastic and more brittle, and increases fracture risk. Further research is warranted to investigate this clinically important interaction and develop therapeutic guidelines integrating calcium supplementation and other nutritional interventions into a comprehensive strategy for treating osteoporosis that mitigates adverse effects and maximizes the therapeutic benefits of sodium fluoride therapy on bone quality.

Physicians prescribing fluoride to enhance bone mass are advised to coadminister calcium (400-500 mg three times daily) but to separate oral ingestion by at least 2 hours to reduce the risk of the two agents interfering with each other's absorption. Weight-bearing exercise, vitamin D, and sunlight exposure are also advisable to support bone health and reduce risk of bone loss.

Sucralfate (Carafate).

Vucelic et al. ²⁶⁸ conducted a clinical trial investigating the effects of sucralfate on serum phosphorus, calcium, and alkaline phosphatase in 30 patients with chronic renal failure on intermittent hemodialysis. They reported an increase in serum calcium (as well as a significant reduction in serum phosphorus and alkaline phosphatase) after 14 days of treatment with sucralfate (1 g four times daily).

Calcium administration requires supervision during sucralfate therapy for hyperphosphatemia and secondary hyperparathyroidism in patients with chronic renal failure; avoidance of calcium may be appropriate in some cases. Physicians prescribing sucralfate should monitor patients for signs of hypercalcemia, which might be induced or aggravated by high calcium intake. Furthermore, serum phosphorus should be checked routinely in patients treated with sucralfate for peptic ulcer disease, although the risk of interference in calcium-phosphorus homeostasis is certainly much lower in patients with normal renal function. In the absence of clinical trial data, clinical vigilance is warranted.

Tamoxifen (Nolvadex).

Tamoxifen preserves BMD in postmenopausal women but may increase bone loss in premenopausal women. ²⁶⁹ Hypercalcemia is a rare adverse effect associated with tamoxifen therapy, the risk of which could theoretically be increased by calcium supplements. Hypercalcemia can occur in any advanced cancer in which the tumor cells make parathyroid-related protein (a peptide hormone), and in such tumors, concomitant calcium could aggravate the condition. However, the only time tamoxifen causes hypercalcemia is in breast cancer patients with bone metastases, who have a “tamoxifen tumor flare” in the first 2 to 3 weeks after initiating tamoxifen therapy; this is caused by the estrogen agonist activity of tamoxifen being asserted before the estrogen antagonist effect takes hold. Tumor flare is well known to be highly predictive of an ultimate therapeutic response in the breast cancer patient. Calcium intake during this brief window of tumor flare might exacerbate the hypercalcemia, but bone (rather than oral intake of calcium) is the primary source of the calcium in such cases. These patients respond to bisphosphonates, such as pamidronate and related drugs, which increase the binding of calcium to the bone matrix and shut down the function of osteoclasts, which are necessary to mobilize calcium from bone.

Calcium supplementation may be appropriate outside this volatile initial phase but must be approached with caution and close monitoring. In the longer term, physicians prescribing tamoxifen for prevention or treatment of breast cancer can enhance the bone health of these patients by recommending adequate calcium and vitamin D intake through dietary and supplemental sources (at appropriate phases in the therapeutic process), encouraging weight-bearing exercise and sunlight exposure and counseling about the relationship between smoking and alcohol and bone loss. Together these prudent recommendations will support overall health and may lessen bone loss and the risk of subsequent osteoporosis. BMD should be measured in women receiving chemotherapy of any type. Strategic integrative protocols, adapted to the characteristics and needs of the individual patient, offer expanded possibilities for enhanced care and improved outcomes within the context of collaborative care involving health care professionals trained and experienced in both conventional oncology and nutritional therapeutics.

Excessive alcohol intake may reduce calcium absorption.

See Caffeine.

Omega-6 fatty acids: Gamma-linolenic acid.

Omega-3 fatty acids: Alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA).

Animal studies and some evidence from human research indicate that essential fatty acids (EFAS) may enhance calcium absorption, at least in part, by enhancing the effects of vitamin D, to reduce urinary calcium excretion, to increase calcium deposition in bone and improve bone strength, and to enhance bone collagen synthesis. ^270-272 Animals deficient in EFAs develop severe osteoporosis with increased renal and arterial calcification. In particular, these effects from the interaction between EFAs and calcium metabolism are associated with reduced ectopic calcification, specifically in the arteries and the kidneys, a major factor in mortality associated with osteoporosis.

In a randomized clinical trial involving 65 postmenopausal women taking a background diet low in calcium, Kruger et al. ²⁷² observed that the coadministration of gamma-linolenic acid (omega-6 fatty acids from evening primrose oil) and eicosapentaenoic acid (omega-3 fatty acids from fish oil) with 600 mg/day calcium carbonate for 18 months was associated with improvements in markers of bone formation/degradation and bone mineral density (BMD), as well as a decreased incidence of fractures. In contrast, Bassey et al. ²⁷³ found no significant benefit in two randomized controlled trials comparing effects of calcium-EFA combination versus calcium alone on BMD in healthy premenopausal and postmenopausal women. The apparent inconsistency between these findings may reflect differences in the ages, general health status, diet, physical activity level, and other influential factors, which were significantly contrasting in the groups of women studied and need to be taken into account in any comparison between the studies and their results. In particular, long-term activity level and nutritional status, especially long-term dietary intake of calcium and EFAs, are known to affect calcium absorption and bone health.

Both calcium and EFAs have beneficial effects on the population with or at risk for osteoporosis. However, further research is warranted to investigate the specific interaction(s) between calcium and EFAs, as well as the mechanisms of action, clinical significance, and therapeutic implications for bone health and other functions and conditions.

Concomitant administration of calcium and iron can decrease GI absorption of iron, particularly from nonheme sources. ²⁷⁴ Calcium supplements inhibit absorption of supplemental iron to a greater degree when taken with food. ^275,276 Evidence, some extrapolated from research involving antacids, suggests that calcium can interfere with the absorption of iron and possibly other minerals by neutralizing stomach acid. ^148,277 However, human research indicates that clinically significant effects on the status of either mineral are improbable, most likely because of compensatory changes in absorption rates. ²⁷⁸ Thus, it is unlikely that iron absorption is significantly reduced when iron and calcium are combined within a multimineral formulation. Nevertheless, when iron and calcium are being taken as separate supplements, separation of intake by 2 or more hours will avoid any impairment of absorption. Furthermore, taking calcium supplements away from meals appears to reduce adverse effects on absorption of iron and possibly other nutrients.

Animal and human studies demonstrate that lysine can enhance intestinal calcium absorption and improve the renal conservation of the absorbed calcium, thus reducing urinary calcium excretion. ^279,280 Coadministration of calcium and L-lysine supplements may provide a synergistic benefit for both preventive and therapeutic interventions in osteoporosis. Further research with well-designed, long-term clinical trials is warranted.

Magnesium intake from food and supplements is associated with BMD. ²⁸¹ Concomitant administration of calcium and magnesium, particularly with high calcium intake, decreases GI absorption of magnesium. However, such competition does not appear to exert clinically significant effects on status of either mineral. ^282-284

Calcium supplementation, as well as cessation of magnesium administration, is typically used in treating hypermagnesemia.

Cow's milk contains a different proportion of various mineral constituents than human milk. In particular, cow's milk, dairy products, and other foods that are high in phosphorus may reduce calcium absorption by forming insoluble complexes with calcium ions. Lactose does not enhance calcium availability in lactose-tolerant individuals. ²⁸⁵ Controversy continues as to whether calcium in many dairy products (1) may have limited bioavailability for individuals who do not properly digest dairy products because they lack sufficient lactase to digest the milk sugar or (2) may react to the characteristic proteins.

Oral administration of calcium, as a divalent cation, may bind with oral phosphate and interfere with phosphorus absorption in the GI tract. ^271,286 Most commentators portray the adverse impact of high phosphorus intake (e.g., in phosphoric acid—containing soft drinks, particularly in association with cola) on calcium function as the more clinically significant adverse effect of this interaction. Nevertheless, contentious debate and unresolved issues characterize the literature concerning the interactions, mechanisms, contextual influences, and clinical implications of high phosphorus intakes on calcium balance and bone health, as well as the impact of calcium on phosphorus balance.

Higher phosphorus intake has been associated with slightly lower levels of urinary calcium but also with slightly increased intestinal secretion of calcium, resulting in increased calcium loss in the feces. ²⁸⁷ Overall, the increase in endogenous fecal calcium from increasing phosphorus is generally about equal to the effect from decreasing urinary calcium. Diets high in phosphorus and low in calcium have been found to increase PTH secretion.

In terms of dietary consumption patterns, phosphorus intake tends to displace calcium intake. Animal protein, dairy products, and many carbonated beverages are especially high in phosphorus. The use of phosphorus-containing food additives contributes substantially to daily phosphorus intake for most people consuming a standard American diet, and their use is increasing, especially in processed foods. In particular, soft drinks often contain phosphoric acid as an acidulant to maintain carbonation, and the link between consumption of soft drinks and bone loss has been the subject of much discussion. Dietary intervention studies have shown that elevations in serum phosphorus resulting from high phosphorus intake may have physiological consequences that are harmful to both bone and kidney when sustained over time and particularly when calcium intake is low. Intake of foods rich in phosphorus (especially as additives) and low in calcium is associated with a persistent elevation in serum PTH levels but no increase in calcitriol (1,25-OH ² D, the active metabolite of vitamin D). ²⁸⁸ Such dietary patterns among children and adolescents do not bode well for long-term risk of osteoporosis in populations eating a standard American diet. ²⁸⁹

One stream of research indicates that calcium intake, especially at relatively high levels, may adversely affect phosphorous balance. Thus, Heaney and Recker ²²⁵ concluded that no net association of different phosphorus intakes with calcium balance was likely because these two effects were opposite in direction. Twenty years later, Heaney and Nordin ²⁹⁰ led a team of researchers investigating the impact of high calcium intake on phosphorus absorption, metabolism, and function. They observed that phosphorus absorption falls and the risk of phosphorus insufficiency rises when calcium intake increases without a corresponding increase in phosphorus intake. In particular, they expressed a concern for dietary intakes with high Ca:P ratios that can occur with use of calcium supplements or food fortificants consisting of nonphosphate calcium salts. These researchers concluded that “older patients with osteoporosis treated with current generation bone active agents should receive at least some of their calcium co-therapy in the form of a calcium phosphate preparation.” ²⁹⁰

Health care professionals concerned with bone health and the unresolved complexities of the interaction between these two important nutrients can most benefit their patients by strongly advocating an active lifestyle supported by a diverse and balanced diet of fresh, nutrient-rich foods and minimal intake of processed foods and soft drinks throughout life, but especially during those life stages emphasizing attainment of maximal bone density and prevention of bone loss. Use of a multimineral formulations containing phosphorus has been recommended for individuals, especially the elderly, regularly taking high doses of calcium. In general, separating intake of supplemental phosphorus from calcium intake, either as calcium-rich foods or supplements, by at least 2 hours will minimize any impairment of absorption of either nutrient.

The effect of dietary protein on calcium balance is often treated as if it were a well-documented phenomenon, but it still remains contentious, seemingly paradoxical, and ultimately unresolved. Increases in dietary protein intake are directly associated with increased urinary calcium excretion and increased risk of bone loss over time. As the intake of dietary protein increases, the urinary excretion of calcium increases as a result of decreased fractional tubular reabsorption, such that doubling protein intake results in a 50% increase in urinary calcium excretion. ²⁸⁷ Using data from Zemel, ²⁹¹ Weaver et al. ²⁹² calculated that each additional gram of protein consumed results in an additional loss of 1.75 mg of calcium per day. Given an average absorption efficiency of 30% for dietary calcium, each 1-g increase in protein intake per day creates a requirement for an additional 5.8 mg of calcium per day to offset the protein-induced calcium loss.

Lifelong high intake of dietary animal protein correlates with increased risk of osteoporosis in most studies. ²⁹³ After sustaining an osteoporotic fracture, however, a 20-g/day supplement of protein reduced bone loss compared with similar patients not supplemented with protein. ²⁹⁴ Another randomized, double-blind trial showed that a supplement of soy protein powder providing 40 g protein and 90 mg soy isoflavones increased BMD at the spine in postmenopausal women. ²⁹⁵

The effect of high protein on bone health remains unclear and controversial. The seemingly inconsistent findings could easily reflect differences in subject characteristics, medical conditions, materials tested, and dosage levels more than they reveal fundamental contradictions. Nevertheless, advising calcium supplementation along with increased dietary protein is probably reasonable. Diets simultaneously high in protein and inadequate in calcium especially may put people at risk for skeletal sequelae, particularly in later life. Furthermore, even though a large proportion of those consuming a standard American diet are more likely at risk of excess protein effects on calcium economy, those with insufficient protein intake are at perhaps greater risk of poor bone health. In particular, serum albumin levels (paralleling protein nutriture) are inversely related to hip fracture risk, and inadequate protein intakes have been associated with poor recovery from osteoporotic fractures. ²⁸⁹

The available evidence suggests that high sodium intake is associated with adverse effects on calcium and increased risk of bone loss. Increased sodium intake results in increased urinary calcium excretion, possibly because of competition between sodium and calcium for reabsorption in the kidney or through an effect of sodium on PTH secretion. ^288,292,296 In a 2-year longitudinal study of the effect of sodium and calcium intakes on regional bone density in 124 postmenopausal women, Devine et al. ²⁹⁷ found that increased urinary sodium excretion (indicative of increased sodium intake) was associated with decreased BMD at the hip. Further research into this important interaction is clearly warranted, particularly given the strong association between diets high in sodium and decreased intake of foods rich in calcium and other beneficial nutrients. ²⁸⁹

Phytic acid can interfere with the absorption of calcium. However, some research shows that soy products have relatively high calcium bioavailability, even though soybeans are rich in both oxalate and phytate. ²⁹² Some health care professionals recommend a 2-hour separation between intake of calcium supplements and eating soya products.

See also earlier Strategic Considerations discussion.

Coadministration of vitamin D and calcium, along with weight-bearing exercise and sunlight exposure, are generally considered the foundational approaches to calcium nourishment, attainment and maintenance of BMD, and prevention of bone loss. ^298-300 A normal physiological function of vitamin D is to facilitate intestinal calcium absorption.

Although findings have varied, often significantly influenced by methodology (especially in meta-analyses), most research indicates that concomitant intake of calcium and vitamin D reduces risk of fractures and enhances bone health, particularly with individuals with a preexisting insufficiency and consistent patient compliance. In general, according to Heaney and Weaver, ⁷⁹ prudent nutritional support for osteoporosis prevention and treatment consists of 30 to 40 mmol calcium daily with sufficient vitamin D to maintain serum 25(OH)D levels above 80 nmol/L (∼25 µg [1000 IU] vitamin D/day). In a Cochrane Library review of 38 randomized or quasi-randomized trials, Avenell and Handoll ³⁰¹ found that the risk of fractures of the hip and other nonspinal bones was reduced slightly in elderly people who are frail and at risk for bone fractures, particularly those who live in nursing homes or other institutions, if vitamin D and calcium were given. Nevertheless, the risk of spinal fractures did not appear to be reduced.

In a trial involving 944 healthy Icelandic adults, Steingrimsdottir et al. ⁸ found that with 25-OHD levels below 10 ng/mL (i.e., significant vitamin D deficiency), maintaining calcium intake above 800 mg/day appeared to normalize calcium metabolism, as determined by the PTH level, but in individuals with higher 25-OHD levels, no benefit was observed from calcium intake above 800 mg/day.

In 2005 and 2006, three major papers were published discussing the relationship between calcium, vitamin D, and osteoporotic fracture risk. Findings from the RECORD study, published in The Lancet(2005), suggested a lack of benefit from concomitant calcium and vitamin D in the prevention of fractures in menopausal women. ⁴⁰ Subsequently, Jackson et al. ³⁰² published a paper using data from the Women's Health Initiative that questioned the assumption that calcium and vitamin D can prevent osteoporosis-related hip fractures. They randomly assigned 36,000 postmenopausal women to receive elemental calcium, as calcium carbonate (500 mg twice daily), plus vitamin D (200 IU twice daily) or a placebo for an average of 7 years. Notably, the average calcium consumption in both groups was approximately 1150 mg/day, close to the appropriate recommended intake level. After 7 years, subjects in the treatment group exhibited 12% fewer hip fractures than did those in the placebo group, a finding that was not statistically significant. However, a deeper analysis of the data reveals that more significant differences appear when considering compliance and initial calcium intake levels. For example, after excluding women who were not adhering to the program, the reduction in fractures was greater, with 29% fewer fractures in the treatment group than in the placebo group, a statistically significant difference. Likewise, hip fracture risk decreased by about 22% in treated subjects whose initial calcium intake was low or moderate, but increased by 12% in treated women with high initial calcium intake (≥1200 mg/day). ³⁰² Overall, in both trials compliance was only on the order of 40% and 50%.

In contrast, Boonen et al. ³⁰³ conducted a multifaceted meta-analysis of major randomized placebo-controlled trials that analyzed the effects of vitamin D alone or in combination with calcium. In one analysis they found that randomized clinical trials comparing vitamin D alone to placebo showed no effect. Likewise, a subsidiary analysis showed that low doses of vitamin D, less than 800 units/day, exerted no effect. However, they demonstrated a statistically significant 21% reduction in risk of fracture, compared to placebo, among subjects receiving 800 IU vitamin D and more than 1000 mg calcium daily. The authors concluded that vitamin D exerts its beneficial effect on bone predominantly by increasing absorption of calcium.

In some individuals and with certain medical conditions, supplementation with vitamin D, particularly at levels significantly in excess of those needed to overcome established deficiency, can induce an excessive increase in the absorption of calcium and increase the risk of hypercalcemia and kidney stone formation. ³⁰² The risk of such adverse effects occurring may be influenced by the form of calcium used, as well as other, individual patient variables. Emerging evidence and the opinions of many vitamin D researchers now suggest, however, that the daily value (DV) of 400 IU for vitamin D, which was based on the amount necessary to prevent rickets in infants (initially given as 5 mL of cod liver oil 100 years ago) is an order of magnitude below the amount necessary for older adults and those not regularly exposed to sun without sunscreen to achieve and maintain blood levels of vitamin D that are optimum for bone health and cancer prevention. ^304-316 “Estimates of the population distribution of serum 25(OH)D values, coupled with available dose-response data, indicate that it would require input of an additional 2600 IU/d (65 mcg/d) of oral vitamin D ³ to ensure that 97.5% of older women have 25(OH)D values at or above desirable levels.” ³¹⁷ Absent lymphoma or granulomatous disease, which can cause vitamin D sensitivity, it appears that long-term ingestion of greater than 10,000 IU/day is necessary to cause vitamin D toxicity and hypercalcemia.

Most available evidence from human studies indicates that simultaneous administration of calcium and zinc decreases GI absorption of zinc. ^275,318-323 Research based on antacids suggests that calcium can interfere with the absorption of zinc (and possibly other minerals) by neutralizing stomach acid. ²⁷⁷ However, clinically adverse significant effects on bioavailability or status of either mineral are improbable. In particular, when ingested in the presence of meals, zinc levels appear to be unaffected by increases of either dietary or supplemental calcium.