P&T News: November 1996
Jacqueline D. Pilzer, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Kenneth G.
Saag, M.D.
This article will briefly review traditional treatments of osteoporosis and will then focus on two new treatment options recently approved by the FDA-alendronate and intranasal calcitonin.
Prevention and Traditional Treatments
The most important preventable cause of fractures is low bone mass.
Various traditional strategies have been used to increase peak bone
mass and/or decrease the rate of subsequent bone loss.
Weight-bearing exercise enhances the development of bone in adolescents and children and may slow bone loss in elderly patients.] In addition, regular exercise promotes mobility, agility, and muscle strength that may help prevent falls.
There is some evidence that peak bone mass can be enhanced by adequate calcium intake.2 It was found that premenopausal women given calcium supplementation did not lose bone, while those given a placebo lost bone from the lumbar spine at a rate of 1% per year. In postmenopausal women, calcium supplementation of 1,000 mg or more per day may decrease postmenopausal bone loss.3 This effect may be more pronounced in women with low baseline calcium intake.2 For these reasons adequate calcium supplementation is recommended as a part of all prevention and treatment programs for osteoporosis (Table 1).1
|
Table 1. Optimal Calcium Requirements | ||
|
POPULATION |
AGE (YEARS) |
ELEMENTAL CALCIUM (mg/day) |
|
Adolescents/Young Adults |
11 to 24 |
1,200 to 1,500 |
|
Men |
25 to 65 |
1,000 |
|
|
more than 65 |
1,500 |
|
Women |
25 to 50 |
1,000 |
|
|
more than 50 (no HRT) |
1,500 |
|
|
more than 50 with HRT |
1,000 |
|
|
more than 65 |
1,500 |
|
|
Pregnant/Nursing |
1,200 to 1,500 |
Vitamin D levels tend to decrease with age.4 This relative vitamin D deficiency is associated with Type I osteoporosis, and some clinicians recommend supplementation with 400 to 800 units of vitamin D per day.4
Sodium fluoride has also been investigated in the treatment of osteoporosis, since it has the ability to stimulate bone formation.5 A four-year study found that treatment with ?5 mg of sodium fluoride daily increased cancellous bone mass with a trend towards decreased fracturing of vertebral bodies.5 The cortical bone mass, however, was decreased and the sites containing cortical or mixed bone became more fragile, resulting in increase in fractures. A later study investigated a lower dose, slow-release fluoride formulation in 110 women over four 14-month cycles.6 Patients received sodium fluoride 25 mg twice daily for twelve months; the last two months of each cycle were drug free. All patients were also taking calcium citrate 800 mg daily. These authors found an increase in spinal and femoral neck density, with a subsequent decrease of new vertebral fractures. There was no change seen in recurrent vertebral fractures and in patients with very low bone density (<65% of young adult mean). This formulation, unlike the immediate-release product, did not increase appendicular fractures. The sustained-release formulation of sodium fluoride is currently still investigational in the U.S.
Estrogen replacement has become the standard of care in the U.S. for preventing and treating postmenopausal osteoporosis and should be considered for all estrogen-deficient women without contraindications to its use. Estrogen use has been associated with lower wrist and non-spinal fractures in women over the age of 65 years., It is, however, most beneficial if started as soon as possible after menopause and is continued indefinitely. Estrogen therapy has also been found to be beneficial in reducing vertebral fractures after one year of treatment in women 47 to 75 years of age with established osteoporosis.8 A three-year follow-up study of these women found a 12% increase from baseline in lumbar spine bone mineral density after two to three years of therapy.9
Alendronate
Alendronate (Fosamax - Merck) is an oral aminobiphosphonate that acts
as a specific inhibitor of osteoclastmediated bone resorption,
resulting in a shift in the balance between bone resorption and
formation towards new bone formation.10 At very high concentrations
(6,000 times the antiresorptive dose), it may also interfere with
crystal formation and mineralization. Alendronate has been marketed
for the treatment of postmenopausal osteoporosis (10 mg per day) and
Paget s disease (40 mg per day). Other bisphosphonate agents that
have been studied for these indications are pamidronate and
etidronate.11-13 These agents, however, are not FDA-labeled for this
indication, possibly due to a less favorable ratio between
suppression of resorption and inhibition of mineralization. 14
Efficacy
Chesnut et al investigated the effect of alendronate on bone mass and
the markers of bone remodeling in a multicenter, double-blind,
placebo-controlled study of 188 postmenopausal women.'5 The women
were between 42 to 75 years of age and at least five years
postmenopausal. Lumbar spine bone mineral density (BMD) was < 0.88
g/cm2 [approximately two standard deviations (SD) below young U.S.
white female mean BMD values]. Patients taking medications such as
corticosteroids or having a disease that affects bone metabolism were
excluded. Patients with a history of spine or hip fractures
attributable to osteoporosis were also excluded. The treatment groups
were: alendronate 5 or 10 mg daily for two years, alendronate 20 or
40 mg daily for one year followed by one year of placebo, or
alendronate 40 mg daily for three months followed by 2.5 mg for 21
months. All patients received a daily supplement of 500 mg elemental
calcium. The investigators found that at each dose alendronate
produced significant reductions in the markers of bone resorption
(urinary deoxypyridinolone/ creatinine) and formation (serum
osteocalcin and alkaline phosphatase). In addition, a significant
increase in bone mass was observed at the lumbar spine, hip and total
body, whereas patients receiving placebo had reduced bone mass at
these sites. The alendronate 10 mg daily group had an increase in BMD
of 7.21% + 0.49% for the lumbar spine, 5.27% + 0.70% for the total
hip, and 2.53% + 0.68% for total body after 24 months of treatment
(each p<0.01); this was compared to decreases of 1.35% + 0.61%,
1.2%+ 0.64%, and 0.31% + 0.44% at these sites, respectively, for the
placebo treatment group. It was noted that in the 5 and 10 mg groups,
progressive and significant improvement in BMD at the spine and the
hip were observed in the second year of treatment (p<0.05). This
increase occurred at a slower rate than in the first year. In those
groups where treatment was discontinued after one year, the benefits
of drug treatment were sustained through the second year of the
study. The rapid decrease in BMD that is observed with estrogen
cessation was not seen in these groups. The authors concluded that
positive BMD changes were associated with daily, rather than
cumulative, dosing of alendronate and that daily doses of 5 to 10 mg
seemed to be optimal.
Liberman et al, in a multicenter, placebo-controlled study of 994 women aged 45 to 80 years, who were at least five years postmenopausal, investigated the effect on BMD and fracture rates with varying doses of alendronate.16 The women had osteoporosis defined as a BMD of the lumbar spine that is at least 2.5 SD below the mean value in premenopausal white women. Women with or without a history, of fractures were selected in an attempt to represent the general population of women with osteoporosis. Women with alternate causes of osteoporosis, such as corticosteroid use or Paget's disease, were excluded from the study. The treatment regimens were 5 or 10 mg daily for three years, or 20 mg daily for two years followed by 5 mg per day for one year. Supplemental calcium (500 mg elemental calcium) was also administered. All treatment groups were found to have increases in the BMD at all skeletal sites at three years, while there was a significant loss in the placebo group. The 10 mg group was as effective as the 20mg/5 mg group, and both were more effective than the 5 mg group. In all three groups the most rapid increase in BMD occurred during the first six months of treatment. In the 10 mg group there was an increase in BMD at all sites in each year, while the other two groups had no further increase during the third year of treatment. This led to the conclusion that 10 mg per day is the optimal dose for the treatment of osteoporosis in postmenopausal women. The mean differences in BMD between the 10 mg and placebo groups was 8.8% +0.4% in the spine, 5.9+0.5% % in the femoral neck, 7.8+0.6% in the trochanter and 2.5+0.3% in the total body. Overall, treatment with alendronate was associated with a 48% reduction in new vertebral fractures [relative risk 0.52 (95% confidence interval 0.28 to 0.95)]. This reduction was found in all women, regardless of age and the presence or absence of previous vertebral fractures. In addition, the risk of a vertebral fracture was decreased in all dosage groups. Among women with new fractures, the proportion of two or more fractures was lower in the alendronate groups. There was a trend towards a reduced number of nonvertebral fractures in the alendronate group, with a cumulative incidence of 8.5% after three years in the alendronate-treated patients and 10.7 % in the placebo arm. The estimated risk of nonvertebral fractures on alendronate was 0.79 (95% confidence interval 0.52 to 1.22).
Tolerability and Precautions
The most common adverse effects that were observed with alendronate
in the clinical trials were abdominal pain, dyspepsia, nausea,
constipation and diarrhea.10 However, these were not statistically
different from the rates of adverse effects observed in the placebo
group.10,16 Since the drug was marketed in the U.S., postmarketing
surveillance has revealed several case reports of esophagitis and
esophageal ulceration.17,18 These reports have resulted in vigorous
efforts to educate health care professionals on the appropriate
instructions that need to be given to patients regarding the
administration of alendronate (Table 2). The dose must be
administered in the morning on an empty stomach with a full glass of
water. The manufacturer has revised the prescribing guidelines to
include the warning that patients with abnormalities of the esophagus
which delay esophageal emptying, such as stricture or achalasia,
should not receive alendronate.18 Concomitant administration of
alendronate with coffee or orange juice decreases its already low
bioavailability of 0.7% by another 60%.'° Patients should not
lie down for at least 30 minutes after taking the dose to minimize
the risk of esophageal irritation, and patients who are unable to
stand or sit upright for this time should not receive the drug.18
Alendronate should also not be used in patients with severe renal
insufficiency (creatinine clearance < 35 ml/min), uncorrected
hypocalcemia, or vitamin D deficiency.
|
Table 2. Patient Information about Alendronate (Fosamax[R])19 |
|
1. Take alendronate on an empty stomach in the morning with a full glass water. Do not take with coffee, orange juice or mineral water. 2. Wait at least 30 minutes before your first meal, beverage or any other medication, including antacids, calcium supplements or vitamins. 3. Do not lie down for at least 30 minutes after taking alendronate. |
Place in Therapy
Alendronate has been shown to significantly increase total body bone
mineral density in women with postmenopausal osteoporosis. In
addition, it has shown a significant decrease in vertebral fracture
rates in these women. Alendronate requires careful patient
counseling; patients with predisposing conditions, such as erosive
esophagitis, may not be good candidates for this drug because of the
potential for esophageal erosions. It should be reserved as
second-line therapy for women with osteoporosis who are unable to
tolerate estrogen therapy or who experience fractures in spite of
hormone replacement. Safety has not been established beyond three
years of treatment. Its efficacy as a preventative agent is currently
being investigated.20
Calcitonin
Calcitonin is a polypeptide hormone produced by the parafollicular
cells of the thyroid gland.21 By decreasing the activity of
osteoclasts, calcitonin decreases bone resorption. For this reason it
has been used to treat several diseases characterized by increased
bone turnover. Recently, a formulation of salmon calcitonin was
developed for nasal administration. This product was approved for the
treatment of postmenopausal osteoporosis (> five years after
menopause) at a dose of 200 IU per day in alternating nostrils.
Efficacy Studies
Overgaard et al studied 208 women 68 to 72 years of age who had a
bone mineral content of the distal forearm of at least two standard
deviations below the mean value for healthy premenopausal women.22
Intranasal calcitonin 50, 100 or 200 IU per day or placebo was
administered for two years. All patients received 500 mg of elemental
calcium daily. There was a significant dose-related response to
calcitonin on the bone mineral content of the spine: an increase of 1
% per 100 IU was noted both after one and two years of treatment (p =
0.07 and p = 0.08). The BMD of the distal forearm decreased by
approximately 1% after two years with no significant difference
between the treatment arms. The parameters of bone turnover plateaued
after one year of treatment. The fracture data were pooled for the
different dosage groups and it was found that the rate of new
patients with fractures and the rates of new fractures were
significantly lower in the calcitonin-treatment groups. The risk
reduction was approximately 66% [relative risk 0.23 (0.07 to 0.77) to
0.37 (0.14 to 0.95)].
Calcitonin has also been investigated in the prevention of postmenopausal lumbar spine bone loss in early postmenopausal women.21 The patients (n=251) were six months to six years postmenopausal (45 to 62 years of age). The women received calcitonin 50 or 200 IU per day or placebo intranasally five days per week for two years. Calcium supplementation was supplied to all patients and vertebral bone mineral density was measured every six months. The placebo group was found to have a decrease in lumbar spine density of 6.28% from baseline (p<0.0001), whereas it increased in the 50 IU calcitonin group by 0.82% from baseline (p=NS) and by 2.03% in the 200 IU group (p < 0.01). There was no difference in the changes between the two calcitonin groups, while each treatment group was significantly different from placebo. The authors concluded that 50 IU of calcitonin administered intermittently via the intranasal route was able to counteract the effect of estrogen withdrawal and prevent lumbar bone loss in early postmenopausal women.
Calcitonin has also been shown to have a positive effect on bone pain in patients with osteoporosis.23 Since the relief of bone pain occurs before the biochemical indexes of bone disease are identified, it has been hypothesized that bone pain relief occurs through an opioid mechanism, rather than via the effect on bone remodeling alone.24
Tolerability and Precautions
Nasal irritation, dryness, and rhinitis have been the most common
complaints with intranasal calcitonin.25 As with all other treatments
for osteoporosis, adequate intake of calcium and vitamin D is
essential with calcitonin.
Place in Therapy
Calcitonin has been shown to counteract bone loss in early menopause.
However, it does not supplant estrogen replacement as the first-line
therapy for this indication and it does not offer the additional
benefits that have been shown to be associated with estrogen therapy
(e.g., cardiovascular benefits). Calcitonin may be used for the
treatment of established osteoporosis, as it has been shown to
decrease fracture rates when used for two years. Its efficacy appears
to be limited in comparison to alendronate (2% increase in BMD after
two years of treatment vs 8% increase in BMD with alendronate
treatment after three years of treatment), but it appears to have a
better safety profile than the bisphosphonate. Intranasal calcitonin
may be a beneficial alternative in patients with established
osteoporosis, who are unable to tolerate alendronate. In addition,
calcitonin may have a role during the immediate postfracture period
due to its analgesic effects.23
Summary
Exercise, adequate calcium and vitamin D replacement and hormone
replacement therapy remain first- line therapy in the prevention of
osteoporosis. Estrogen and calcium are relatively inexpensive as well
(Table 3). Provided there are no contraindications, women should
begin hormone replacement as soon as possible after menopause and
continue therapy indefinitely for maximum benefit.
Table 3.Dose and Cost of Medication Therapy for Osteoporosis
|
DRUG |
DOSE |
AWP flor One Month of Therapy |
|
Alendronate* (Fosamax[R]) |
10 mg po daily |
$50 |
|
Calcitonin intranasal* (Miacalcin[R]) |
200 IU per day |
$50 |
|
Calcium
|
1,000 to 1,500 mg of elemental calcium daily |
$4 $4 $4
$11 |
|
Estrogens#
|
0.625 mg daily
0.5 mg po daily 0.05 mg weekly |
$13
$8 $19 |
|
Vitamin D* |
400 to 800 IU daily |
$1 to 2 |
At this time there are insufficient data to recommend alendronate or intranasal calcitonin in the primary prevention of osteoporosis. Alendronate and intranasal calcitonin should be used in women who have low bone mineral density or fractures in spite of hormone replacement therapy or in women with osteoporosis in whom hormone replacement is contraindicated. Alendronate seems to be slightly more effective in increasing bone mineral density than intranasal calcitonin when the relative increase in bone mineral density is assessed, but it has a higher potential for gastrointestinal adverse effects which may preclude its use in certain women. Intranasal calcitonin is well tolerated and may have some benefits in patients with acute pain due to osteoporosis.
References
DRUGS ADDED TO STOCK
ADDITIONAL ACTIONS
DRUGS DELETED FROM STOCK
Nefazodone has been shown in vitro to be an inhibitor of cytochrome P450IIIA4 Cisapride, like terfenadine and astemizole, is metabolized by the cytochrome P450IIIA4 isoenzyme. Increased plasma concentrations of these agents are associated with QT prolongation and with rare cases of serious cardiovascular adverse events, including death, due principally to ventricular arrhythmia of the torsades de pointes type. Consequently, the contraindication to coadministration of nefazodone and cisapride has been added to the prescribing information for nefazodone; the contraindication to the coadministration of nefazodone with terfenadine and astemizole was previously listed. However, these contraindications do not yet appear in the most current prescribing information for astemizole, terfenadine, or cisapride.
Source: Bristol-Myers Squibb Company
December 1995
The agency has taken steps to have the package insert revised for the following fluoroquinolones: ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, and ofloxacin. Letters have been issued to the manufacturers requesting that they revise package inserts to include the following information:
Also, as an added precaution, the following statement will be added to the "Information for Patients" subsection of the PRECAUTIONS section:
Source: JAMA 1996;276:774.
AUGMENTIN[R] DOSING CONVERSION CHART*
|
ADULTS |
|
| |
|
8 hour dosing |
12 hour dosing |
|
250 mg amoxicillin/125 mg clavulanate |
500 mg amoxicillin/125 mg clavulanate |
| |
|
8 hour dosing |
12 hour dosing |
|
*500 mg amoxicillin/125 mg clavulanate |
*875 mg amoxicillin/125 mg clavulanate |
|
PEDIATRICS (Patient is more than 12 weeks old and weighs less than 40 kg) | |
| |
|
8 hour dosing |
12 hour dosing |
|
*20 mg/kg/day |
*25 mg/kg/day |
| |
|
8 hour dosing |
12 hour dosing |
|
*40 mg/kg/day |
*45 mg/kg/day |
PRODUCTS AVAILABLE ON FORMULARY AT UICH AFTER JANUARY 2, 1997
|
Augmentin[R] Product |
Clavulanate Content |
|
Suspension# |
|
|
57 mg per 5 ml |
|
Chewable Tablets |
|
|
28.5 mg |
|
Tablets |
|
|
125 mg |