(British Approved Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects, Treatment, and Precautions

Acute infusion reactions during or within 1 to 2 hours of infusion are common with infliximab, and other TNF inhibitors, particularly with the first or second dose. Symptoms include fever, chills, pruritus, urticaria, dyspnoea, chest pain, and hypertension or hypotension. Mild reactions may respond to a reduced rate of infusion or a temporary interruption. If reactions are more severe, therapy should be stopped. Pretreatment with paracetamol, corticosteroids, and antihistamines may be considered. TNF inhibitors should only be given where facilities for resuscitation are available. Delayed reactions have occurred 3 to 12 days after infliximab treatment symptoms include myalgia, arthralgia, fever, and rash. Similar delayed reactions may also be seen when infliximab has been restarted after an extended period without treatment (see below). Other, common, adverse effects include nausea and vomiting, abdominal pain, diarrhoea, fatigue, dizziness, headache, and back pain. Antibodies to infliximab (human antichimeric antibodies) may develop, and are associated with an increased incidence of hyper sensitivity reactions. Antinuclear antibodies and anti-double-stranded-DNA antibodies have also developed with TNF inhibitor therapy. A lupus-like syndrome has occurred rarely treatment should be stopped if it develops.

Infections are common in patients treated with infliximab or other drugs that inhibit TNF, and most often affect the upper respiratory tract and the urinary tract. TNF inhibitors have also been associated rarely with the development of serious opportunistic infections, sepsis, pneumonia, and onset or reactivation of tuberculosis (see below), particularly in patients with underlying conditions predisposing them to infections in some cases death has resulted. TNF inhibitors should not be given to patients with severe infection, including active tuberculosis, abscesses, and opportunistic infections, and should be stopped if these develop. Patients should be evaluated for latent and active tuberculosis before beginning therapy if evidence of latent tuberculosis is found, the risks and benefits of treatment should be considered carefully and chemoprophylaxis should be started before giving a TNF inhibitor. They should also be used with care in those with chronic infections, a history of recurrent infections, or with underlying conditions that may predispose to infections. Patients with fistulising Crohn’s disease with suppurative fistulas should not be given infliximab until possible infection sources such as abscesses have been ruled out. Patients should be instructed to seek medical advice if symptoms suggestive of tuberculosis (such as persistent cough, weight loss, or low grade fever) occur. Patients should be monitored for signs of infection after stopping treatment: for adalimumab and infliximab, which both have long half-lives, monitoring should continue for 5 or 6 months, respectively because of its relatively shorter half-life, the elimination of etaner-cept may be quicker.

There have been rare reports of severe hepatic reactions such as acute liver failure, jaundice, hepatitis, and cholestasis with infliximab some cases have been fatal or required transplantation. Patients with signs or symptoms of hepatotoxicity should be evaluated and infliximab should be stopped in those patients with jaundice or marked elevations in liver enzyme values. Infliximab and other TNF inhibitors have also been associated with the reactivation of hepatitis B in chronic carriers, which has resulted in fatalities in some cases. Patients at risk of hepatitis B infection should be screened before starting treatment it is recommended that carriers treated with a TNF inhibitor are closely monitored during, and for several months after stopping, treatment.

Blood dyscrasias, including leucopenia, thrombocytopenia, pancytopenia, and aplastic anaemia, have been reported rarely with TNF inhibitors in some cases the outcome was fatal. They should be used with caution in patients with a history of blood dyscrasias. Rare, and sometimes fatal, cases of interstitial lung disease including pulmonary fibrosis and pneumonitis have been reported with TNF inhibitors. Infliximab and other TNF inhibitors are also associated with an increased incidence of malignancies including lymphoma (see also Carcinogenicity, below), although occurrences are rare. Some groups of patients treated with TNF inhibitors may already have an increased background risk of developing malignancies, regardless of drug treatment. Care has been advocated in patients with a history of malignancy. Anaphylactic reactions have been reported rarely with TNF inhibitors. Infliximab should be avoided in patients with a history of hyper sensitivity to the drug or other murine proteins.

TNF inhibitors have been associated in rare cases with seizures and clinical or radiological worsening of demyelinating disorders such as multiple sclerosis or optic neuritis care is required in prescribing it to patients with such disorders or symptoms suggestive of their onset.

Worsening and, in some cases, new-onset heart failure has been reported with TNF inhibitors (see Effects on the Heart, below). (NYHA class III or IV). In the UK, infliximab is contra-indicated in patients with moderate to severe heart failure however, US licensed product information advises that doses up to 5 mg/kg may be used in such patients. It should be used with caution in patients with mild heart failure (NYHA class I or II). All patients with heart failure should be closely monitored and infliximab stopped in those who develop new or worsening symptoms of heart failure. Similar recommendations are given for the TNF inhibitors adalimumab and etanercept, although UK licensed information for etanercept only advises caution in patients with heart failure.

Carcinogenicity. Malignancies, especially lymphomas, have been seen in patients treated with TNF inhibitors for rheumatoid arthritis and Crohn’s disease however, the suggestion of a causal relationship is controversial. A meta-analysis in 2006 identified 24 published reports of malignancies in 3493 study patients with rheumatoid arthritis who had received at least one dose of a TNF inhibitor (adalimumab or infliximab) along with 2 cases in 1512 control patients further, unpublished, cases were also found using FDA data to give 29 malignancies in the treatment groups and 3 in the control groups. Based on these figures, there was a 3.3-fold increase in the risk of malignancy in patients receiving TNF inhibitors when compared with controls. These results have, however, been criticised on a number of points including the difficulty in applying them to current practice because etanercept was not included in the analysis, and, in particular, the unexpectedly low rate of malignancies in the control groups. Other studies in patients with rheumatoid arthritis’ and Crohn’s disease have generally concluded that the overall risk of malignancies is not significantly increased in patients taking TNF inhibitors when compared with patients who have not taken these drugs. Some studies’ in patients with rheumatoid arthritis have, however, shown a possible increased risk of lymphoma with TNF inhibitor treatment, but caution in interpreting these results was recommended as they were based on a small number of cases in addition, the background risk of lymphoma is increased in rheumatoid arthritis regardless of treatment. The risk of malignancies with TNF inhibitors requires further study. Rare cases of hepatosplenic T-cell lymphoma have been seen in adolescents and young adults given infliximab for the treatment of Crohn’s disease. In July 2006, the manufacturer was aware of 6 cases of this type of lymphoma in 5 adolescents aged 12 to 19 years and one 31 -year-old adult 4 of the 6 cases occurred in males. The treatment duration ranged from 1 or 2 infusions to over 4 years of therapy in all cases, patients were also taking or had taken azathioprine or 6-mercaptopurine. This type of lymphoma is aggressive and 5 of the above patients died. A causal relationship was not clearly established although it could neither be excluded. Further cases have since been reported.

Delayed reactions. Ten of 37 patients with Crohn’s disease retreated with infliximab after a 2 to 4 year period without treatment had delayed hypersensitivity reactions, of which 6 were considered serious. None of the patients had had infusion-related adverse effects with their original infliximab therapy. Adverse reactions developed in 9 of the 23 patients originally treated with a discontinued liquid formulation, and in 1 of the 14 patients who previously received the marketed formulation, leading to speculation that the formulation may have been a contributing factor.

Effects on blood lipids. A 35-year-old man with psoriatic arthritis and psoriasis developed markedly elevated triglyceride levels and a mildly increased total cholesterol level after a single infusion of infliximab tests prior to therapy had shown a mild hypertriglyceridaemia for which he had received no treatment. No further doses of infliximab were given and his triglyceride levels subsequently improved.

Effects on the CNS. Aseptic meningitis developed in a patient after his fifth injection of infliximab for rheumatoid arthritis. Similar symptoms also occurred after a sixth injection. Two patients with inflammatory bowel disease developed acute motor neuropathy with multiple conduction blocks following infliximab treatment both patients improved after infliximab was stopped. Similar adverse effects were reported in 2 further patients : one was taking etanercept for rheumatoid arthritis and the other infliximab for ankylosing spondylitis. Three cases of bilateral optic neuropathy associated with infliximab therapy have also been reported. Other neuropathies have been associated with TNF inhibitor treatment, including Guillain-Barre syndrome.

Effects on the heart. The FDA has reported on 47 patients who developed heart failure during long-term therapy with TNF antibodies (etanercept and infliximab) for arthritic conditions or Crohn’s disease. Of these, 38 developed new-onset heart failure, 19 having documented risk factors for heart failure, and 9 had exacerbation of existing heart failure. The median time to new-onset heart failure was 3.5 months. However, studies investigating a possible association between TNF inhibitors and the development of heart failure have been equivocal and further investigation is warranted.

Preliminary investigations on the use of infliximab in the treatment of moderate to severe heart failure failed to show any clinical improvement in patients given infliximab 5 mg/kg or 10 mg/kg when compared with placebo in addition, those given the higher dose had an increased risk of death or hospitalisation due to worsening heart failure.

Effects on the lungs. Infliximab treatment has been associated with a fatal exacerbation of previously asymptomatic fibrosing alveolitis in 3 patients with chronic rheumatoid arthritis all 3 patients were also taking azathioprine and prednisolone. There was no evidence of infection or other underlying causes for the decline in respiratory function.

Effects on the skin. Patients with rheumatoid arthritis receiving TNF inhibitor therapy are more likely to develop adverse skin reactions than those who are not. Of 289 patients taking TNF inhibitors (infliximab, etanercept, adalimumab, and lenercept), 72 (25%) reported 128 dermatological events including skin infections, eczema, drug-related eruptions, and malignancies such as actinic keratosis of the 289 patients not taking TNF inhibitors, 37 (13%) reported dermatological events. In another review, cutaneous adverse effects were seen in 35 out of 150 patients receiving TNF inhibitors (adalimumab, etanercept, or infliximab) for rheumatic disorders cases included dermatitis herpetiformis and leucocytoclastic vasculitis although eczematous and skin infections were more common or infectious. Perhaps unexpectedly, psoriasis-like lesions were seen in 8 patients, 6 of whom had no history of psoriasis similar effects have also been noted in other patients with rheumatoid arthritis or Crohn’s disease.

Rare cases of serious skin reactions have been associated with TNF inhibitor treatment. Since approval in 1998, the FDA has received 15 cases of erythema multiforme, 5 cases of Stevens-Johnson syndrome, and 1 case of toxic epidermal necrolysis associated with infliximab cases for etanercept, approved in the same year, included 13 reports of erythema multiforme, and 4 reports each of Stevens-Johnson syndrome and toxic epidermal necrolysis. For adalimumab, which was marketed late in 2002, there have been 4 cases of erythema multiforme and 2 of Stevens-Johnson syndrome.

Infection. There have been spontaneous reports of onset or reactivation of tuberculosis in patients treated with infliximab, including cases of miliary tuberculosis and unusual extrapulmo-nary disease. The UK CSM noted in February 2001 that there had been 28 such reports worldwide. The US manufacturers subsequently reported (in October 2001) that other serious opportunistic infections, including histoplasmosis, listeriosis, and pneumocystosis had occurred, and had led to some deaths the number of reported cases of tuberculosis had risen to 84. Further opportunistic infections also continued to be reported FDA data up to August 2002 included reports of candidiasis, coccidioidomycosis, nocardiosis, aspergillosis, and infections due to non-tuberculous mycobacteria. Health Canada reported in October 2004 that it had received 188 and 109 reports of infections associated with infliximab and etanercept, respectively, from January 2000 to May 2004. Of these, 10 and 2 reports were of tuberculosis associated with infliximab and etanercept, respectively. The FDA also received 25 reports of tuberculosis associated with etanercept between November 1998 and March 2002. Although the majority of patients also had a history of treatment with im-munosuppressants including corticosteroids, the inhibition of TNF may affect normal immune responses and predispose patients to opportunistic infections.

Guidelines have been issued by the British Thoracic Society to quantify the risks of reactivation of tuberculosis with TNF inhibitors and to advise on the treatment of such infection in patients being assessed for TNF inhibitor therapy.

Interactions

Live vaccines should not be given with infliximab or other drugs that inhibit TNF as the effect of such drugs on vaccine efficacy or the risk of infection transmission is unknown. The use of TNF inhibitors with the interleukin-1 receptor antagonist anakinra may increase the risk of serious infections and neutropenia such combinations are not recommended. A similar interaction has been seen with TNF inhibitors and the co-stimulation blocker abatacept.

Abatacept. Use of the TNF inhibitor etanercept with abatacept has resulted in an increase in the incidence of serious adverse effects including serious infections in addition, there was no increase in clinical benefit. Combinations of abatacept with TNF inhibitors are not recommended by UK licensed product information.

Anakinra. The incidence of serious infections, injection site reactions, and neutropenia is increased when anakinra is given with the TNF inhibitor etanercept. In addition, the combination did not provide any further clinical benefit when compared to etanercept alone. Similar findings may be expected if anakinra is given with other TNF inhibitors.

Pharmacokinetics

Infliximab shows linear pharmacokinetics. It is distributed primarily in the vascular compartment and, after single doses, has a terminal elimination half-life of 8 to 9.5 days. After repeated doses, infliximab has been detected in serum for at least 8 weeks.

Uses and Administration

Infliximab is a chimeric monoclonal antibody to tumour necrosis factor a (TNF), a pro-inflammatory mediator. Elevated levels of TNF have been found in the affected tissues and fluids of patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, and Crohn’s disease and ulcerative colitis. Elevated TNF levels are also found in psoriatic plaques. Infliximab is given by intravenous infusion over a usual period of not less than 2 hours shorter infusion times have been used in some patients with rheumatoid arthritis (see below for further details).

Infliximab is used with methotrexate in the management of moderate to severe, active rheumatoid arthritis to reduce the signs and symptoms of the disease, delay structural damage, and improve physical function in the UK it is licensed for use in patients who have had an inadequate response to standard disease-modifying antirheumatic drugs (DMARDs) although, in severe progressive cases, it may be used in patients not previously treated with methotrexate or other DMARDs in the USA it may be used for treating early rheumatoid arthritis. Infliximab is given in a dose of 3 mg/kg, repeated at 2 and 6 weeks, then every 8 weeks thereafter. For the first 3 doses infliximab should be infiised for at least 2 hours however, UK licensed product information suggests that subsequent infusion times may be reduced to a minimum period of 1 hour in those who tolerate the initial infusions. A clinical response is usually achieved within 12 weeks of starting treatment.

Patients with an inadequate response during this period or who later relapse may benefit by increasing the dose: in the UK, a maximum dose of 7.5 mg/kg every 8 weeks (with increases made in steps of 1.5 mg/kg) is recommended whereas, in the USA, a maximum dose of 10 mg/kg is allowed. Alternatively, a dose of 3 mg/kg may be given as often as every 4 weeks in such patients. Continuing therapy in those who show no response within the first 12 weeks of treatment or after dose adjustment should be carefully reconsidered: in the UK NICE recommends that infliximab be withdrawn if there is no adequate response within 6 months of starting treatment. Patients with moderate to severe, active Crohn’s disease unresponsive to conventional treatment may be given a single infliximab dose of 5 mg/kg. This may be followed by a maintenance regimen of additional infusions of 5 mg/kg at 2 and 6 weeks after the initial infusion and then every 8 weeks, or the drug may be read-ministered when signs and symptoms of the disease recur (but see below). UK licensed product information does not recommend further doses in patients who are unresponsive after the first 2 doses in the USA, a patient is not considered to be unresponsive until 3 doses have been given. A similar regimen is used in patients with fistulising Crohn’s disease although therapy should not be considered ineffective until after the third dose of infliximab. US product information suggests that doses of up to 10 mg/kg may be used in patients who relapse after an initial response. Infliximab is also used in the treatment of moderate to severe, active ulcerative colitis in patients unresponsive to conventional therapy the recommended dose is 5 mg/kg given as a regimen similar to that used for Crohn’s disease (see above). Therapy should not be considered ineffective until after the third dose of infliximab.

In the treatment of ankylosing spondylitis, UK licensed product information recommends that infliximab should only be used in patients with severe disease who have had an inadequate response to conventional treatment however, in the USA it may be used in early treatment, to reduce the signs and symptoms. The initial dose is 5 mg/kg, repeated at 2 and 6 weeks and then every 6 to 8 weeks if there is no response after 2 doses no further treatment should be given.

Infliximab is also used in the treatment of active and progressive psoriatic arthritis in the UK, its use is limited to patients who have had an inadequate response to standard DMARD but, as before, US licensed product information allows earlier use. In the USA, it may be given with or without methotrexate however, UK product information only recommends use without methotrexate in those patients who are intolerant of or have contra-indications to such treatment. It is given in a single dose of 5 mg/kg, repeated at 2 and 6 weeks and then every 8 weeks thereafter. Guidance issued by NICE in the UK recommends that treatment with infliximab is stopped after 12 weeks in those who show an inadequate response. Infliximab is used in the treatment of moderate to severe plaque psoriasis. Its use is usually limited to patients in whom other treatments are not suitable. Infliximab is given in a dose of 5 mg/kg, repeated at 2 and 6 weeks, then every 8 weeks thereafter. Treatment should be stopped after 14 weeks (4 doses) in patients who show no response.

If the signs and symptoms of rheumatoid arthritis or Crohn’s disease recur infliximab may be readminis-tered if within 16 weeks of the last infusion. Readministration after a drug-free interval of more than 16 weeks may be associated with an increased risk of delayed hypersensitivity (see Delayed Reactions, above) and consequently is not recommended. Recommendations regarding the readministration of infliximab for other indications (other than those detailed above) have not been established. Limited data from readministration with a single dose of infliximab in psoriasis after an interval of 20 weeks suggest reduced efficacy and a higher incidence of mild to moderate infusion reactions when compared with the initial regimen. For details of infliximab use in children, see below.

Administration in children. Infliximab is licensed for use in moderate to severe, active Crohn’s disease in children aged 6 years and over who have not responded to conventional therapy, or who have contraindication for or are intolerant of such treatments doses are the same as those used in adults (see above). UK licensed product information suggests that the dosage interval may be adjusted to maintain any benefits however, further treatment is unlikely to be of use in patients not responding within the first 10 weeks.

Although unlicensed for such use in the UK, infliximab has also been used in children with fistulising Crohn’s disease the BNFC recommends that those aged 6 to 18 years may be treated with the same dosage regimen that is used for this indication in adults (see above).

Asthma. TNF inhibitors such as infliximab have been investigated in the treatment of refractory asthma. There is some evidence that only a minority of patients will respond to such therapy, and that the benefits and risks must therefore be carefully assessed.

Inflammatory bowel disease. Infliximab is used in adults for the treatment of Crohn’s disease and ulcerative colitis (see Inflammatory Bowel Disease) it has also been used in children in the treatment of inflammatory bowel disease, particularly Crohn’s disease.

In the treatment of Crohn’s disease, guidance issued in the UK by NICE recommends that infliximab is used in patients with severe disease when treatment with immunomodulators and corticosteroids has failed or is not tolerated, and when surgery is inappropriate.

In the treatment of ulcerative colitis, guidance issued by NICE recommends against the use of infliximab in subacute manifestations of moderately to severely active disease (defined as that which would normally be managed in an outpatient setting, and does not require hospitalisation or the consideration of urgent surgical intervention). The use of infliximab in acute manifestations of moderately to severely active ulcerative colitis is under review by NICE.

Leprosy. Infliximab has been used in the treatment of recurrent type 2 (erythema nodosum leprosum) lepra reactions (see Leprosy). However, 2 cases of rapidly progressive leprosy developing in patients given infliximab for rheumatoid arthritis have also been described reversal (type 1) reactions occurred in both when infliximab was stopped.

Psoriasis. Infliximab is used in the treatment of moderate to severe plaque psoriasis. In the UK, NICE recommends that it be reserved for severe cases, unresponsive to standard therapies (including ciclosporin, methotrexate, and PUVA) or where such therapies cannot be used.

Rheumatoid arthritis. TNF inhibitors play an increasingly important role in the management of rheumatoid arthritis they tend to be reserved for patients who are unresponsive to more conventional disease-modifying drugs, although some favour use earlier in management.

Some references to the use of infliximab in rheumatoid arthritis and juvenile idiopathic arthritis.

Sarcoidosis. For a mention of possible benefit from infliximab in sarcoidosis.

Spondyloarthropathies. References to the use of infliximab in the treatment of ankylosing spondylitis and psoriatic arthritis. In the UK, NICE considers that TNF inhibitors should be reserved for severe active psoriatic arthritis unresponsive to at least 2 standard disease-modifying drugs etanercept or adalimumab are preferred to infliximab.

Uveitis. Infliximab has been tried with some success in the treatment of uveitis including that associated with Behcet’s syndrome. Uveitis can also develop as a complication of other inflammatory disorders such as rheumatoid arthritis treatment with infliximab may improve ocular symptoms in addition to its effect on the primary disorder. References.

Vasculitic syndromes. For a preliminary report on the use of infliximab in Takayasu’s arteritis. Infliximab has also been investigated in the management of Kawasaki disease in patients who are unresponsive to standard treatment.

Proprietary Preparations

Argentina: Remicade † Revellexl

Australia:: Remicade

Belgium: Remicade

Brazil: Remicade

Canada: Remicade

Chile: Remicade

Czech Republic: Remicade

Denmark: Remicade

Finland: Remicade

France: Remicade

Germany: Remicade

Greece: Remicade

Hong Kong: Remicade

Hungary: Remicade

Indonesia: Remicade

Ireland: Remicade

Israel: Remicade

Italy: Remicade

Japan: Remicade

Malaysia: Remicade

Mexico: Remicade

The Netherlands: Remicade

Norway: Remicade

New Zealand: Remicade

Philippines: Remicade

Poland: Remicade

Portugal: Remicade

Russia: Remicade

South Africa: Revellex

Singapore: Remicade

Spain: Remicade

Sweden: Remicade

Switzerland: Remicade

Thailand: Remicade

Turkey: Remicade

UK: Remicade

USA: Remicade

Venezuela: Remicade

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects and Precautions

As for Infliximab.

Injection site reactions including erythema, itching, pain, and swelling are the most common adverse reactions with adalimumab however, most reactions are mild and do not result in drug withdrawal. Other common reactions include headache, rashes, back pain, hypertension, paraesthesias, increased alkaline phosphate levels, and cough. Autoantibodies to adalimumab have been detected.

Interactions

As for Infliximab.

Methotrexate is reported to reduce the clearance of adalimumab by up to 44% but licensed product information for the latter states that dosage adjustment for either drug does not appear to be necessary.

Pharmacokinetics

Adalimumab is reported to have linear pharmacokinetics at usual dosages. After subcutaneous injection peak concentrations are reached in about 3 to 8 days and bio-availability is estimated to be 64%. The mean terminal half-life is about 2 weeks.

Uses and Administration

Adalimumab is a recombinant human monoclonal tumour necrosis factor (TNF) antibody that binds specifically to TNF-a and blocks its interaction with endogenous cell-surface TNF receptors. It also modulates biological responses that are induced or regulated by TNF. Elevated levels of TNF have been found in the affected tissues and fluids of patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and Crohn’s disease. Adalimumab is used in the treatment of moderate to severe, active rheumatoid arthritis and active and progressive psoriatic arthritis to delay structural damage and improve physical function. In the UK, it is licensed for use in patients who have had an inadequate response to standard disease-modifying antirheumatic drugs (DMARDs), although in severe progressive rheumatoid arthritis it may be used in patients not previously treated with methotrexate in the USA, it may be used to reduce the signs and symptoms of early disease. Adalimumab is also used in the treatment of active ankylosing spondylitis: UK licensed product information recommends that it should only be used in patients with severe disease who have had an inadequate response to conventional treatment however, in the USA it may be used to reduce signs and symptoms in early disease. For all the above indications, it is given by subcutaneous injection in a dose of 40 mg every other week. In the treatment of rheumatoid arthritis, UK licensed product information recommends that adalimumab should be given with methotrexate, although monotherapy may be used where treatment with methotrexate would be inappropriate. When used as monotherapy in rheumatoid arthritis, some patients may benefit from increasing the dose to 40 mg every week. Clinical response is usually achieved within 12 weeks of treatment.

Adalimumab is also used in the treatment of moderate to severe, active Crohn’s disease unresponsive to conventional treatment it may also be used in patients who have relapsed while taking infliximab. Patients may be given an initial dose of 160 mg on day 1 (given as four 40-mg injections in one day or two 40-mg injections daily for 2 consecutive days), followed by 80 mg two weeks later (day 15). After a further two weeks (day 29), a maintenance dose of 40 mg every other week may be started. Alternatively, UK licensed product information advises that patients at risk of adverse effects may be given 80 mg initially, followed by 40 mg 2 weeks later thereafter, usual maintenance doses may be given. A clinical response is usually seen within 12 weeks of starting treatment those patients who relapse while on adalimumab may benefit from increasing the maintenance dose to 40 mg every week. In the treatment of moderate to severe chronic plaque psoriasis in patients unresponsive to, or intolerant of, conventional systemic therapy including phototherapy, the recommended initial dose of adalimumab is 80 mg subcutaneously this may be followed by a maintenance dose of 40 mg subcutaneously on alternate weeks, starting 1 week after the initial dose. A clinical response is usually seen within 16 weeks of starting treatment.

For the uses of adalimumab in children, and recommended doses, see below.

Administration in children. In the USA, adalimumab is licensed in the treatment of moderate to severe, active juvenile id-iopathic arthritis in children aged 4 years and above: it may be used alone or with methotrexate. The dose is calculated according to weight and is given subcutaneously: those weighing 15 kg to less than 30 kg should be given 20 mg every other week, while heavier children may receive 40 mg every other week.

Inflammatory bowel disease. Adalimumab is used in the management of Crohn’s disease, including in patients who are intolerant of, or relapse on, infliximab treatment. It has also been tried in the treatment of ulcerative colitis.

Psoriasis. Adalimumab is used in the treatment of plaque psoriasis.

Rheumatoid arthritis. References to the use of adalimumab in rheumatoid arthritis.

Spondyloarthropathies. References to the use of adalimumab in ankylosing spondylitis and psoriatic arthritis (see Spondyloarthropathies).

Uveitis. Adalimumab has been tried with some success in the treatment of idiopathic uveitis. Uveitis can also develop as a complication of other inflammatory disorders such as rheumatoid arthritis treatment with adalimumab may improve ocular symptoms in addition to its effect on the primary disorder.

Proprietary Preparations

Argentina: Humira

Australia: Humira

Belgium: Humira

Brazil: Humira

Canada: Humira

Chile: Humira

Czech Republic: Humira

Denmark: Humira

Finland: Humira

France: Humira

Germany: Humira

Greece: Humira

Hong Kong: Humira

Hungary: Humira

Ireland: Humira

Israel: Humira

Italy: Humira

Malaysia: Humira

Mexico: Humira

The Netherlands: Humira Trudexa

Norway: Humira

New Zealand: Humira

Poland: Humira

Portugal: Humira

Singapore: Humira

Spain: Humira

Sweden: Humira

Switzerland: Humira

UK: Humira

USA: Humira

Venezuela: Humira

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects and Precautions

Acute infusion reactions occurring within 1 hour of starting an infusion are common with abatacept use. The most frequently reported infusion events are dizziness, headache, and hypertension hypotension and dyspnoea occur less commonly. Other acute events include nausea, flushing, pruritus, rash, and wheezing. Most events are usually mild to moderate although stopping treatment may be necessary in a few patients. Other common adverse effects include headache, na-sopharyngitis, nausea, dyspepsia, diarrhoea, dizziness, back pain, fatigue, cough, and abnormal liver function values. Antibodies to abatacept may develop and ana-phylaxis or anaphylactic reactions have been reported rarely. Uncommon adverse reactions include paraes-thesia, thrombocytopenia, and leucopenia. Infections are frequent in patients treated with abatacept and most often affect the respiratory and urinary tracts. More serious infections such as pneumonia, sepsis, cellulitis, bronchitis, diverticulitis, and acute pyelonephritis have also been rarely associated with abatacept treatment. Treatment should be stopped in patients who develop a serious infection. Abatacept should not be given to patients with severe and uncontrolled infections such as sepsis and opportunistic infections. It should be used with caution in patients with a history of recurrent infections, with underlying conditions that may predispose to infections, or with chronic, latent, or localised infections. Patients should be screened for latent tuberculosis before starting treatment those testing positive should be treated with standard chemoprophylaxis before beginning abatacept.

Some disease-modifying antirheumatic drugs have been associated with hepatitis B reactivation licensed product information for abatacept recommends screening for viral hepatitis before starting treatment. Adverse effects of abatacept are more frequent in patients with chronic obstructive pulmonary disease and may include a worsening of their respiratory symptoms.

Carcinogenicity. The role of abatacept in the onset of malignancies such as lymphoma in humans is not known.

In placebo-controlled studies the overall frequency of malignancies in patients treated with abatacept compared to those that received placebo was similar (1.4% and 1.1 %, respectively). However, there were more cases of lung cancer and lymphomas in those given abatacept. In animal studies in mice, increases in lymphomas and mammary tumours have been noted, although these increases have not been seen in some studies with other mammals.

Interactions

Live vaccines should not be given with abatacept, or within 3 months of stopping it, as its effect on vaccine efficacy or the risk of infection transmission is unknown. The use of TNF inhibitors with abatacept may increase the risk of serious infections such combinations are not recommended. Use with anakinra or rituximab is also not recommended because of insufficient evidence to assess safety.

Pharmacokinetics

Abatacept is reported to have linear pharmacokinetics at usual dosages. After repeated intravenous doses, its mean terminal half-life is about 13 days. Studies in animals suggest that abatacept is distributed into breast milk.

Uses and Administration

Abatacept, a fusion protein, is a co-stimulation blocker. It prevents the activation of T-cells activated T-cells have been found in the synovium of patients with rheumatoid arthritis. It is used in the treatment of moderate to severe active rheumatoid arthritis to delay structural damage and improve physical function. In the UK, it is licensed for use in patients who have had an inadequate response to standard disease-modifying antirheumatic drugs (DMARDs), including at least one TNF inhibitor in the USA, it may be used to reduce the signs and symptoms of early disease.

Abatacept is given by intravenous infusion over a period of 30 minutes in the following doses, based on body-weight:

• 500 mg for patients weighing less than 60 kg

• 750 mg for those weighing 60 to 100 kg

• 1 g for those over 100 kg.

The dose is repeated at 2 and 4 weeks, then every 4 weeks thereafter. If a response to treatment is not seen within 6 months, the benefits of continuing abatacept may need to be considered. In the UK, abatacept is licensed for use with methotrexate however, in the USA it may be given alone or with other DMARDs (but see Interactions, above).

For the use of abatacept in children, and recommended doses, see below.

Abatacept is also being studied for other auto-immune diseases such as inflammatory bowel disease, psoriatic arthritis, and SLE.

Administration in children. In the USA, abatacept is licensed in the treatment of moderate to severe, active juvenile idiopathic arthritis in children aged 6 years and above it may be used alone or with methotrexate. The dose is calculated according to body-weight and is given as an intravenous infusion over 30 minutes those weighing less than 75 kg should be given 10 mg/kg initially, while heavier children may receive the appropriate adult dose (see above). Doses should be repeated at 2 and 4 weeks, and then every 4 weeks thereafter.

Rheumatoid arthritis. References to the use of abatacept in rheumatoid arthritis.

Proprietary Preparations

Argentina: Orencia

Czech Republic: Orencia

France: Orencia

Portugal: Orencia

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Other Mechanisms Inducing Hypocalcemia

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

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

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

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

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

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

Lifestyle Choices That Induce Bone Loss

Excessive alcohol use and smoking have been associated with osteoporosis.

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

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

Conclusion

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

Glucocorticoid Therapy and Bone Loss

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

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

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

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

Anticoagulants and Bone Loss

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

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

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

Agents That Impair Absorption of Calcium

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

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

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

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

Table 2: Mechanisms of Action Associated with Drug-Induced Bone Disease
Proposed Mechanism	Associated Agents	Specific Medications
Promotion of calcium excretion	Loop diuretics Saline infusions Glucose loading osmotic diuretics Aminoglycosides Growth hormone Prostaglandins Thyroid hormones Aluminum-containing antacids Total parenteral nutrition Potassium-sparing diuretics	Furosemide (Lasix), Bumetanide (Bumex), ethacrynic acid (Edecrin) Mannitol, sucrose, urea Gentamicin (Garamycin), amikacin (Amikin), tobramycin (Nebcin), netilmicin (Netromycin) Somatropin (Nutropin, Protropin, Saizin) Alprostadil (Prosin VR, Caverject, Edex) Levothyroxine (Levoxyl, Synthroid) Aluminum hydroxide (Amphojel) Triamterene (Dyrenium)
Inhibition of bone turnover	Retinoic acid derivatives Aminoglycosides Alkylating agents	Retinoin (Retin-A) Gentamicin (Garamycin), amikacin (Amikin) tobramycin (Nebcin), netilmicin Cisplatinum (Platinol), carboplatin (Paraplatin)
Direct inhibition of osteoclastic activity	Antineoplastic agents	Mithramycin (plicamycin, Mithracin)
Reduction in rate of osteoblastic/osteoclastic activity	Aluminum	Aluminum hydroxide (Amphojel)
Reduction in calcium absorption	Corticosteroids Lubricant laxatives Diphenylmethane laxatives Barbiturate anticonvulsants Sodium polysulfonated    polystyrene resin	Prednisone, dexamethasone, triamcinolone (Azmacort) Mineral oil (Agoral Plain) Phenolphthalein (Feen-a-Mint, Ex-Lax) Phenobarbital (Luminal) Kayexalate, SPS
Interference with renal activation of Vitamin D	Anticoagulants Corticosteroids	Heparin Prednisone, dexamethasone, triamcinolone (Azmacort)
Interference with Vitamin D metabolism	Anticonvulsants Ethanol Hypnotics	Phenytoin (Dilantin) phenobarbital (Luminal) Glutethimide (Doriden)
Reduction in serum magnesium levels secondary to renal tubular damage	Aminoglycosides Antiprotozoal, antibiotic Immunosuppressants Antifungal agents Ethanol	Gentamicin (Garamycin), amikacin (Amikin), tobramycin (Nebcin), netilmicin (Netromycin) Pentamidine (Pentam) Cyclosporine (Sandimmune, Neoral, Sangcya) Amphotericin B (Fungizone)
Impaired Vitamin D absorption	Antilipemic	Cholestyramine (Questran), Colestipol (Colestid)
Complexation of calcium	Chelating agents Ammonium detoxicants Phosphate supplements Antivirals Blood products (calcium citrate)	Edetate disodium (EDTA, Endrate, Chealamide) Neomycin (Mycifradin) Sodium/potassium phosphate salts (K-Phos, Neutra-Phos, Fleet Enema) Foscarnet (Foscavir)
Reduction in parathyroid hormone secretion	Aluminum Ethanol	Total parenteral nutrition, aluminum hydroxide (Amphojel)
Impaired calcium absorption secondary to decreased gastric pH and impaired fat breakdown	H2-blockers	Cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid)

Agents That Impair Absorption of Vitamin D

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

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

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

Agents That Cause Secondary Impairment of Vitamin D

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

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

Osteoporosis, Osteopenia, Osteomalacia

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

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

Agents Needed for Bone Maintenance

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

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

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

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

Calcium plus estrogen leads to stronger bones.

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