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In 1969, Novartis developed an injectable concentration of calcitonin-salmon for use in the treatment of osteoporosis.
This new drug became available in the United States in 1984
1995 the FDA had approved a new, more convenient form of calcitoninsalmon: MIACALCIC® Nasal Spray.
This formulation is indicated for the treatment of post-menopausal osteoporosis in women at least 5 years postmenopause who refuse or cannot tolerate estrogens or for whom estrogens are not an option.
As a result of these innovations, and with the recent additions of other treatment options, osteoporosis is no longer seen as merely an unfortunate consequence of aging; it is now a treatable medical disease.
The socioeconomic costs of osteoporosis are extensive.
Social costs include pain, emotional stress, deformity, immobility and death.
It is estimated that osteoporotic fractures result in 40,000 to 50,000 deaths in the United States each year.
Monetary costs of osteoporosis and osteoporosis-related fractures, which include the cost of hospitalization and nursing home care, were estimated to be $17 billion in 2001 ($47 million per day) in the United States alone.
Hip fractures have the greatest social and economic impact of all osteoporotic fractures, producing substantial disability and mortality.
This type of fracture often requires lengthy hospitalization and, at times, surgery.
More than half of osteoporosis-related hospitalizations
Clearly, postmenopausal osteoporosis is an extremely prevalent disease, impacting millions of lives with potentially serious consequences. Although currently less than 15% of postmenopausal women receive medication for osteoporosis, this number is expected to grow rapidly in the coming years, due to, in large part, to the marketing and selling efforts of MLACALCIC Nasal Spray and its competitors.
Emotional stress Disability Home healthcare Loss of productivity Rehabilitation Decreased quality of life Extensive hospitalization Pain
The storage and release of calcium ions influence many vital bodily functions, including the structure of bone:
Calcium is critical to maintaining the strength, hardness, and rigidity of bone.
Important in several electrophysiological reactions, which are basically electrical reactions associated with bodily functions. These include the mechanisms that control cardiovascular and neuromuscular function.
Calcium works in conjunction with many enzymes and hormones to execute important biochemical reactions in the body, such as those that control the ability of substances to pass through cell membranes.
Figure 1-2 shows the location of these 2 types of bone tissue in a long bone (femur) and a vertebra. As you can see, cortical bone, or compact bone, generally comprises the outside portion of each bone. This is referred to as the cortical envelope. Although it has some vascularization (that is, it contains blood vessels), cortical bone appears uniformly dense and hard. Approximately 75% to 80% of the skeleton is cortical bone. A relatively higher amount is found in the appendicular skeleton.
Bone modeling is the process by which the skeleton grows to adult size and shape.
As each bone in the skeleton grows, its size and shape are adjusted to respond to mechanical stresses.
Bone modeling is determined primarily by genetic influences , but can also be affected by other factors, such as general nutrition , the amount of calcium ingested, and the level of physical activity .
Even after reaching its adult size, a bone continuously changes in response to changing stresses and demands.
Not only is the bone material constantly breaking down and being reabsorbed into the blood, it is also continuously being re-formed.
Bone quality, on the other hand, refers to the architecture, turnover, damage accumulation, and mineralization of the bone.
It is possible that in some patients osteoporosis is not only the result of bone loss but may be the result of accumulated microfractures, sub-optimal bone development during childhood or adolescence, or other factors affecting bone quality.
However, BMD accounts for about 70% of bone strength.
Clinically, the pronounced loss in BMD associated with osteoporosis presents as an increased risk of fracture—bones may fracture under stress simply because bone loss has become so great.
Osteoporotic fractures, particularly in the early stages of osteoporosis, may be very small (microfractures) and may cause little or no pain.
Osteopenia is a less severe decrease in BMD, which is greater than 1 SD but less than 2.5 SD below the average BMD of healthy, young adults.
Clinically, osteopenia often goes undetected because bone loss has not progressed to the degree where fractures occur.
In terms of the fracture threshold, patients with osteoporosis have crossed the threshold, and patients with osteopenia will cross the threshold at some point in the future unless something prevents further bone loss.
Drugs that affect bone metabolism, such as corticosteroids and thyroid hormone, may lead to osteoporosis.
New research suggests that prolonged steroid use affects the life cycle of bone cells.
High doses of steroids not only reduce the number of bone-forming cells but also cause them to die prematurely.
Secondary osteoporosis can occur in both sexes, and in children as well as adults.
Characteristics of Primary (Postmenopausal and Senile) and Secondary steoporosis Any age Usually after age 75 10 years after menopause (often begins 55-60; can begin earlier) Age of onset chronic disorder, chronic use of certain drugs (ie. Corticosteroids) Old age, age- related Disorders Menopause, estrogen deficiency, genetic Predisposition, dietary and lifestyle factors Reasons Male/Female Male/Female Female Sex Secondary Senile Postmenopausal
Paget’s disease is a chronic bone disorder with accelerated and irregular bone turnover primarily due to overactive osteoclasts and evidenced by extremely high serum concentrations of the enzyme alkaline phosphatase, often reaching twice the normal level.
There is also secondary osteoblast hyperactivity, in which the body apparently attempts to compensate for the marked resorption.
The resulting increase in bone turnover leads to irregularly structured bone tissue that is larger than normal and mechanically weak.
Patients with Paget’s disease are susceptible to fracture.
Dual x-ray absorptiometry (DXA), or dual-energy x-ray absorptiometry (DEXA), determines bone mass by measuring the decrease in the strength of radiation that passes through tissue at the site being evaluated.
DXA is the preferred method of bone densitometry because it allows precise measurement of BMD at both the hip and spine as well as the whole body.
Single x-ray absorptiometry (SXA), which uses technology similar to DXA, is available to measure peripheral sites of the skeleton with relatively constant soft tissue thickness and composition, such as the heel or forearm.
Unlike T-scores, Z-scores always indicate whether or not the BMD is lower than it should be for a patient’s age and sex.
Nevertheless, T-scores are used more often so it’s important to know that a T-score lower than -2.5 on a standard DXA scan shows that the patient has osteoporosis and pharmacologic intervention may be considered to prevent fractures.
A T-score between -1 and -2.5 shows that a patient is osteopenic and pharmacologic therapy may be considered depending on the patient’s overall risk profile.
The principle underlying this technique is that the speed at which ultrasound (high-frequency) sound waves move through bone is determined by the density and inherent material quality (i.e, ability to resist fracture) of bone.
The higher the bone density, the higher the speed of ultrasound.
Bones with high US velocity are high in strength and resist fracture when force is applied.
In contrast, bones with low US velocity deform more with force and are less able to resist fracture.
The broadest definition of a candidate for bone mass measurement, as suggested by the International Society for Clinical Densitometry, is any patient, regardless of age or gender, if the final result of the test will influence a clinical decision.
Typically, however, the indications for bone mass measurement are more specific.
Also, clinical studies are currently’ being conducted to evaluate the use of parathyroid hormone (PTH) as an anabolic therapeutic agent for the treatment and prevention of osteoporosis.
Pharmacologic Preventive and Therapeutic Modalities
Candidates for prevention therapy include:
Those with clinical risk factors for osteoporosis such as Caucasian or Asian descent
slender body build
early estrogen deficiency
smoking alcohol consumption
family history of osteoporosis.
results of densitometry indicating low (BMD) stand deviation <2.5 SD below the mean for healthy young women or analysis of biochemical markers suggesting high bone turnover are also risk factors to be considered.
Pharmacologic Preventive and Therapeutic Modalities
MIACALCIC Nasal Spray, Evista, Fosamax, and Actonel are indicated for the treatment of osteoporosis in postmenopausal women.
Candidates for osteoporosis treatment include patients with very low BMD (>2.5 SD below the premenopausal mean) or with a previous fracture.
Use of Pharmacologic Agents in the Management of Postmenopausal Osteoporosis
*In 2000, the FDA clarified that estrogen is not indicated for the treatment of osteoporosis due to the lack of supporting data. Therefore, estrogen is only approved for the prevention of osteoporosis. Adequate amounts of calcium and vitamin D intake are recommended with all therapies.
Yes Yes Raloxifene Yes Yes Risedronate Yes Yes Alendronate No* Yes Estrogen Yes No Calcitonin-salmon injection Yes No Calcitonin-salmon nasal spray Indicated for treatment Indicated prevention Drug
The hormone estrogen plays an important role in calcium metabolism and exerts a strong stabilizing effect upon bone mass.
Estrogen replacement therapy (ERT), or hormone replacement therapy (HRT), which is a combination of estrogen and progesterone, is often used to compensate for the drop in estrogen production at menopause.
Estrogen therapy’ is used to manage postmenopausal symptoms (eg, hot flashes), as well as to prevent or delay osteoporosis.
Currently; several estrogens are commercially available.
If progesterone (progestin) is used concurrently with estrogen (hormone replacement therapy or I-JRT), the risk of endometrial cancer becomes negligible.
Data from a study conducted by the Women’s Health Initiative (WHI) suggest that other risks may outweigh the benefits of this combination therapy.
In fact, one arm of the planned 8-year study, designed to focus primarily on the prophylactic benefit of HRT (Prempro TM ) provided in 1 daily tablet containing conjugated equine estrogen (CEE) 0.625 mg and medroxy progesterone acetate (MPA) 2.5 mg on cardiovascular disease, was discontinued in June 2002 after only 5 years because of the increased incidence of invasive breast cancer.
Most common side effects with nasal spray: rhinitis and other nasal symptoms; occasionally therapy has to be discontinued due to nasal bleeding or ulcerations
Most common side effects with injectable: nausea, local inflammatory reactions at the site of injection, and flushing of the face or hands; side effects tend to dissipate in the course of treatment and are dose-related
To stabilize bone mass and increase bone mineral density
Use in osteoporosis
Inhibits osteoclast activity
May increase osteoblast activity
Calcitonin-salmon nasal spray: second-line therapy to estrogen in treatment of osteoporosis in women >5 years postmenopause
There are 3 types of calcitonin: salmon, eel, and porcine.
All forms are available in Europe, but only calcitonin-salmon is currently available in the United States.
Calcitonin-salmon is used in conjunction with calcium and vitamin D supplements for the treatment of post-menopausal osteoporosis.
Effects of bisphosphonates on bone mass and fracture risk
Data from large US and multinational studies demonstrated that alendronate (Fosamax, Merck) significantly increased spinal, hip, and total body bone mass in postmenopausal women with osteoporosis over a period of 3 years.
Results also showed that the proportion of women with new vertebral fractures was reduced by 47%.
Risedronate (Actonel, Procter & Gamble and Aventis Pharmaceuticals as co-marketers) is indicated for the prevention and treatment of postmenopausal osteoporosis.
A large multinational and North American study of women with established osteoporosis showed that risedronate 5 mg daily increases BMD at the spine, nonvertebral, and wrist compared to placebo over a 3-year period of time.
Three-year results also demonstrated a decrease in the risk of new vertebral fractures by 41% to 49%.
Effects of bisphosphonates on bone mass and fracture risk
The risk of new vertebral fractures was significantly reduced by 65% within the first year of treatment with risedronate compared to placebo.
These data allowed Actonel to position itself at launch as a rapidly acting bisphosphonate.
The risedronate clinical trials included 60% of patients who used nonsteroidal anti-inflammatory drugs (a frequent cause of GI complications) or aspirin regularly and 40% who had ongoing GI diseases such as ulcers, esophagitis, and heartburn.
The results showed that the incidence of GI side effects in risedronate-treated patients was similar to placebo-treated patients.
Effects of bisphosphonates on bone mass and fracture risk
Therefore, Procter & Gamble was also able to stress that risedronate was well-tolerated even in patients with GI disease.
However, like alendronate, risedronate has the same complex dosing requirements, which may have an impact on patient compliance.
Nevertheless, the risedronate clearly indicates that bisphosphonates may cause upper gaslromtestinal disorders such as dysphasia, esophagal, and esophageal or gastric ulcers.
It also stresses the importance of taking the medication as instructed to minimize the risk of these adverse events.
Fosamax and Actonel tablets must be taken on an empty stomach at least 30 minutes before the first food, beverage, medication, or dietary supplements of the day, with at least 6 to 8 ounces of plain water.
In addition, patients must remain upright for at least 30 minutes after taking the drug.
Contraindications include esophageal abnormalities such as stricture that slows down emptying of the esophagus, inability to stand or sit upright for at least 30 minutes, hypersensitivity to any component of the medication, and hypocalcemia.
Because these drugs are eliminated by the kidney, they are not recommended for patients with severe kidney disease (creatinine clearance <35mL/min).
Selective Estrogen Receptor Modulattws (SERMs) are “designer” estrogens that demonstrate estrogen agonist effects on the skeletal and cardiovascular systems with estrogen antagonist effects on breast and uterine tissue.
They are referred to as SERMs because they have selective effects on estrogen target tissues.
They were developed to provide the benefits of estrogen therapy without the risks. There are new SERMs currently under development.
Evista® (raloxifene hydrochloride, Eli Lilly) is the first SERM approved for the prevention and treatment of osteoporosis.
Similar to estrogen, Evista decreases bone resorption and overall bone turnover as evidenced by decreases in levels of urine and serum biochemical markers of bone turnover.
The biologic activity of Evista is carried out through binding to estrogen receptor, which regulate gene expression.
Selective Estrogen Receptor Modulators
The Use of SERMs in the Treatment and Prevention of Osteoporosis Oral 60-mg tablet Mode of administration Common adverse event considered to be drug related: Hot flashes (menopausal side effects) Leg cramps Precautions about use in patients with a history of thromboembolic events. Safety A selective estrogen receptor mediator Binds to estrogen receptors Reduces resorption of bone Decreases overall bone turnover Effects Prevention and treatment of postmentopausal osteoporosis Bone disease indications Raloxifene: (Evista, Eli Lilly) Available agents in United States
Clinical data from a 3-year, multicenter, randomized, double-blind trial Multiple Outcomes of Raloxifene Evaluation (MORE) indicate that raloxifene (Evista) increases BMD by about 2%.
Compared to estrogen, these increases are smaller.
However, the MORE study results also demonstrate that raloxifene reduces the risk of new vertebral fractures in patients with preexisting fractures by 30%.
Evista also has nonskeletal benefits similar to estrogen, demonstrating decreases in total cholesterol and LDL or “bad” cholesterol. However, unlike estrogen, Evista does not increase HDL or “good” cholesterol.
MIACALCIC Nasal Spray is indicated for the treatment of postmenopausal osteoporosis in women who are more than 5 years postmenopause with low bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated.
Like the injectable formulation of MIACALCIC Nasal Spray contains a synthetic calcitonin similar to the calcitonin found in salmon.
Called salmon calcitonin or calcitonin-salmon, this synthetic polypeptide has 32 amino acids (the building blocks of proteins) lined up in the same sequence as in the calcitonin produced by salmon.
MIACALCIC Nasal Spray is an effective treatment for postmenopausal osteoporosis.
In 2 clinical studies of healthy volunteers, administration of MLACALCIC Nasal Spray (100 to 1600 IU) caused rapid and sustained small decreases in both total serum calcium (calcium in the blood) and serum ionized calcium, although values still remained within the normal range.
Hypocalcemia (abnormally low levels of calcium in the blood) has not been reported in any study of healthy volunteers or postmenopausal women.
Five double-blind, randomized, parallel, placebo-controlled studies involving 551 patients treated for 1 to 2 years served as the basis for the original FDA submission for MIACALCIC Nasal Spray and led to its approval in the treatment of postmenopausal osteoporosis.
Daily therapy with MIACALCIC Nasal Spray (200 LU, or one spray, once a day, anytime, anywhere) consistently increased BMD of lumbar vertebrae compared to baseline and placebo in osteoporotic women who were more than 5 years postmenopause; patients receiving 200 IU MIACALCLC Nasal Spray showed increased lumbar vertebral BMD of 1.4% versus baseline and 3.1% versus placebo at 24 months
Statistically’ significant increases in lumbar vertebral BMD occurred as early as 6 months after starting MLACALCIC Nasal Spray therapy
The overall improvement in lumbar vertebral BMD was 2% to 3% in patients treated daily with 200 IU of MIACALCIC Nasal Spray compared to patients who received calcium and nasal placebo over a 24-month period.
This gain of 2% to 3% in vertebral BMD is comparable to that seen in postmenopausal osteoporotic women treated with estrogen therapy for similar periods of time
While not designed to detect differences in fracture rates, 1 study showed that the incidence of patients with new vertebral fractures was about two-thirds less in patients treated with MJACALCIC Nasal Spray than in patients treated with placebo.
This difference was statistically significant, however, given that these results were derived from pooled data across the 3 dosage groups studied (50 IU, 100 IU, and 200 IU), and that this methodology was not stated from the outset, this information was not permitted as part of our labeling
In 1 clinical study, a statistically significant increase in hip BMD was seen after 1 year of treatment, changing to a trend at 2 years that was no longer statistically significant
*Intent-to treat patients are patients who take at least 1 study dose of medication and show an efficacy end point (i.e., 1 follow-up x-ray). Per protocol patients are patients who take the required amount of study medication to completion of the trial. Because 200 LU is the approved dosing for MIACALCIC Nasal Spray, this section will focus on the results demonstrated in the 200 IU group compared with the placebo group after 5 years of treatment.
Intent-to-treat patients* experienced a 35% reduction in the risk of multiple (2 or more) new vertebral fractures (P=.13)
Per protocol patient's experienced a 45% reduction in the risk of developing multiple (2 or more) new vertebral fractures (P=.06)
Although not statistically significant, a 48% reduction in hip fractures was observed in the 200 IU group (n=5/315) vs placebo (n=9/305) in the “intent-to-treat” population.
However, a larger study would be needed to adequately assess reduction of hip fracture
Additional Findings Not Statistically Significant
A subgroup analysis of patients over 75 years of age showed a 62% risk reduction (P=.03) in the number of new vertebral fractures with 200 IU of MIACALCIC Nasal Spray (12/58) relative to placebo (19/47)
At 3 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 37% Patients with > 1 new vertebral fracture (%) Placebo 200 IU salmon calcitonin NS 37% p=0.037 Stock et al., JBMR 1997, 12(1)
At 5 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 36% in Women With 1-5 Prevalent Vertebral Fractures at Baseline Patients with > 1 new vertebral fracture (%) Placebo 200 IU salmon calcitonin NS 36% p=0.03 Chesnut et al., AJM 2000, Vol 109, 267-276
At 5 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 33% All Patients (%) Placebo 200 IU salmon calcitonin NS 33% p=0.03 Chesnut et al., AJM 2000, Vol 109, 267-276
200 IU Salmon Calcitonin NS is Effective Across All Age Groups
A post-hoc stratification of the PROOF data was carried out to test the hypothesis that salmon calcitonin NS would be a particularly effective and safe therapy to prevent vertebral fractures in women above 70 years of age
Vertebral fracture reduction was calculated using odds ratio analysis
At 5 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 53% in Women >70 Years Women >70 years with > 1 new vertebral fracture (%) Placebo 200 IU salmon calcitonin NS 53% p=0.012 Silverman et al., Third Amsterdam menopause symposium abstract book 2001, page 91
At 5 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 62% in Women >75 Years Women >75 years with > 1 new vertebral fracture (%) Placebo 200 IU salmon calcitonin NS 62% p=0.028 Silverman et al., JBMR 2001, 16(1), S530
200 IU Salmon Calcitonin NS is Effective Across All Age Groups 1,2 0 5 10 15 20 25 30 35 45 40 36%* 53%* 62%* Calcitonin Placebo Primary analysis Patients with 1-5 Vertebral fractures Post-hoc analysis All patients > 70 All patients > 75 *p<0,05 Patients (%) with vertebral fractures 1. Chesnut et al., AJM 2000, Vol 109, 267-276. 2. Silverman et al., JBMR 2001, 16(1), S530
Effect of Salmon Calcitonin NS* on Hip Fracture at 3 Years Placebo Salmon calcitonin NS* Patients with hip fracture (%) 72% P=0.046 Silverman et al., Third Amsterdam menopause symposium abstract book 2001, page 91 *combined 100 IU and 200 IU doses
Effect of Salmon Calcitonin NS* on Hip Fracture at 5 Years Placebo Salmon calcitonin NS* Patients with hip fracture (%) 68% p=0.047 Silverman et al., Third Amsterdam menopause symposium abstract book 2001, page 91 *combined 100 IU and 200 IU doses
Currently the concept of “bone quality” is put to test with QUEST (Qualitative Effects of Salmon-Calcitonin Therapy).
QUEST is a double-blind, placebo-controlled, 2-year study designed to evaluate the effects of MIACALCIC Nasal Spray on bone quality, bone mineral density, and bone turnover in postmenopausal women with 1 to 5 new vertebral fractures.
The only contraindication for MIACALCIC Nasal Spray is clinical allergy to the active ingredient calcitonin-salmon.
Because calcitonin-salmon is a protein, there is the possibility that a systemic allergic reaction could occur in response to this agent
More than 13.4 million prescriptions have been written for MIACALCIC Nasal Spray since its launch in late 1995.
Only a few cases of systemic allergic reactions attributable to the nasal spray formulation have been reported.
If it is suspected that a patient might have sensitivity to calcitonin, skin testing with a small amount of injectable calcitonin-salmon should be considered before starting MIACALCIC Nasal Spray therapy.
If a patient develops severe ulcers in the nasal mucosa (eg, larger than 1.5 mm in diameter or penetrating below the mucosa) or heavy bleeding, treatment with MIACALCIC Nasal Spray should be discontinued.
Smaller ulcers often heal without interrupting MIACALCIC Nasal Spray therapy, although it is recommended that the medication be temporarily discontinued until healing occurs.
There are no adequate and well-controlled studies of calcitonin-salmon therapy in children or pregnant women.
Compared to injectable calcitonin-salmon, MIACALCIC Nasal Spray has fewer troublesome adverse effects.
For example, MIACALCIC Nasal Spray therapy is associated with a lower incidence of nausea (1.8% vs 10%) and flushing (1% vs 2% to 5%) than injectable calcitonin-salmon.
In the pivotal trials discussed in the current package insert, the overall incidence of adverse reactions with MIACALCIC Nasal Spray’ was low and not much greater than that seen with placebo.
Most adverse reactions were mild to moderate in severity. Nasal adverse events were most common, with 70% mild, 25% moderate, and 5% severe in nature (vs placebo rates of 71 % mild, 27% moderate, and 2% severe).
*Symptom of nose includes: nasal crusts, dryness, redness or erythema, nasal sores, irritation, itching, thick feeling, soreness, pallor, infection, stenosis, runny/blocked, small wound, bleeding wound, tenderness, uncomfortable feeling, and sore across bridge of nose.
4.6 3.2 Headache 4.6 3.5 Epistaxis 5.3 3.8 Arthralgia 2.3 5.0 Back pain 16.0 10.6 Symptom of nose* 6.9 12.0 Rhinitis % of Patients % of Patients Adverse reaction N= 341 N= 341 Placebo MIACALCIC Nasal Spray
The unopened bottle should be refrigerated at 36T to ~ (2~C to 8~C) and protected from freezing.
After a pump has been activated, the solution is stable at room temperature and should be maintained at room temperature until the medication has been completed (a period of 2 weeks).
MIACALCIC Nasal Spray is safe and well tolerated.
MIACALCIC Nasal Spray vs Injectable 2-ml vials containing 200 IU per mL Metered-dose solution in 2ml bottles, Delivers 200 IU per spray How supplied 100IU (SC or IM) every other day (for postmenopausal osteoporosis). 200 IU per day, administered Instranasally Dosage and Administration Systemic effects (eg, flushing, nausea). Local effects (eg, rhinitis and other symptoms of the nose) Adverse reactions 3% compared to injectable Biovailability Treatment of postmenopausal osteoporosis, symptomatic Paget’s disease of bone, and hypercalcemia. Treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause with low bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated Indication MIACALCIC Injection MIACALCIC Nasal Spray
Leading Products to Manage Postmenopausal Osteoporosis
To achieve optimum preventive benefit with ERT, it is advised that women begin therapy within 5 years of menopause and continue therapy indefinitely because some studies have found that upon discontinuation, bone loss recurs.
Evista, a SERM, is indicated for the prevention and treatment of postmenopausal osteoporosis.
The results of a 3-year, multicenter, randomized, double-blind, placebo-controlled study demonstrated a modest increase in spinal BMD of approximately 2% with the use of Evista compared with placebo (P<.00 1); results for hip and total body BMD were similar.
Fosamax has also been shown to prevent postmenopausal bone loss.
Results from a 3-year, multicenter, double-blind, placebo-controlled trial demonstrated that at 36 months, patients receiving Fosamax 5 mg had a mean increase in spinal BMD of approximately 3% to 4%; in contrast, patients receiving placebo lost approximately 3% to 4% of BMD at the spine. R
Results for other sites (ie, hip) were similar for the Fosamax- and placebo-treated groups.
A 5-mg once-daily or a 35-mg once-weekly dose of alendronate is approved for the prevention of osteoporosis.
Actonel, a bisphosphonate, has also been shown to prevent bone loss in postmenopausal women.
Results from a 2-year double-blind placebo-controlled study of women within 3 years of menopause (age range 42 to 63 years) indicate that 5 mg of risedronate daily produced significant mean increases in BMD at the lumbar spine, femoral neck, and trochanter compared with placebo.
MIACALCIC Nasal Spray (calcitonin-salmon) is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated.
Ellerington and colleagues (1996), demonstrated a mean increase in spinal BMD of 1.4% vs baseline, in addition to a mean increase in spinal BMD of 3.1% vs placebo.
In another clinical trial, Overgaard (1992), demonstrated a mean increase in spinal BMD of approximately 3% vs baseline.
Although not designed primarily to detect differences in fracture rates, this study demonstrated a reduction in the rate of new vertebral fractures of approximately two thirds when data from all MJACALCIC Nasal Spray treatment groups were pooled.
Results of the 5-year PROOF study, which evaluated 1255 postmenopausal osteoporotic women with 1 to 5 preexisting vertebral fractures at baseline, confirmed the results of this study by demonstrating a significant reduction in the risk of new vertebral fractures (36%).
Although not statistically significant, the PROOF study also showed a 48% reduction in the risk of hip fractures; 1.6% (5/315) of patients in the 200-lU group vs 3.0% (9/305) of patients in the placebo group experienced a hip fracture.
This study suggests a protective effect of MIACALCIC Nasal Spray on hip fractures. However, the study was not designed to detect differences in hip fracture rates, and a much larger patient population is required to quantif~,i such differences.
Fosamax (alendronate) is indicated for the treatment of osteoporosis in postmenopausal women, which may be confirmed by detection of low bone mass or by the presence or history of osteoporotic fracture.
Fosamax therapy has been shown to increase BMD of the hip and spine as well as reduce the risk of fracture.
A multicenter study including 881 women followed for 3 years assessed the effect of Fosamax on the risk of vertebral fractures.
Subjects were 45 to 80 years of age and at least 5 years postmenopause at entry. The results of this study demonstrated a 48% reduction in the risk of new vertebral fractures in women treated with Fosamax.
Similarly, the first arm of the multicenter FIT study, assessing the impact of Fosamax on fracture reduction, showed a 47% reduction in the risk of new vertebral fractures.
Actone1 (risedronate) is indicated for the treatment of osteoporosis in postmenopausal women.
The fracture efficacy of Actonel 5 mg daily in the treatment of osteoporosis was determined in 2 large, randomized, placebo-controlled studies that enrolled approximately 4000 postmenopausal women with established osteoporosis.
The multinational study (VERT MN) was primarily conducted in Europe and Australia, and the North American study (VERT NA) was conducted in the United States and Canada.
The primary end point for these studies was to determine the incidence of new and worsening vertebral fractures over a period of 0 to 3 years.
Within 1 year of treatment, risedronate demonstrated a 65% reduction in the risk of new vertebral fractures compared with placebo (2.4% risedronate-treated patients vs 6.4% placebo-treated patients, a 4% reduction in absolute risk).
However, after 3 years of treatment, the relative risk of fracture was reduced by 41%.
Risedronate also showed a statistically significant increase in BMD at the spine, hip, and wrist compared with placebo.
The efficacy of Actonel for preventing hip fractures was recently evaluated by the Hip Intervention Program (HIP) Study Group.
Participants in this randomized, placebocontrolled study included women between 70 and 79 years old who had osteoporosis and women at least 80 years old who had at least 1 non-skeletal risk factor for hip fracture or a low BMD at the femoral neck.
Participants received either 2.5 mg or 5 mg risedronate, or placebo.
Approximately 4600 women completed 3 years of treatment Risedronate significantly reduced the risk of hip fracture by approximately 30% for women between 70 and 79 who participated in the study.
Patients with no previous fractures were about half as likely to experience a new spinal fracture.
In addition, this study has shown no difference in the proportion of women reporting hip fractures (nontraumatic, nonspine fractures) among those receiving Evista (8.5%) and those receiving placebo (9.3%).
MIACALCIC Nasal Spray can be used anytime, anywhere, offering reliable absorption and efficacy for typical postmenopausal osteoporosis patients (eg, those with age-related issues).
Because of its safety profile and complicated dosing restrictions, Fosarnax may not be ideal for patients who have gastrointestinal (GI), esophageal, or renal disorders, who take multiple medications, who have set daily routines, who have difficulty remaining upright, or who have mental disabilities that preclude them from following the dosing instructions without supervision.
Miacalcic NS vs Fosamax tabs Stops bone loss; helps build bone mass; reduces risk of fractures (vertebral, hip, wrist) Stops bone loss; helps build bone mass Efficacy Prevention of osteoporosis in post-menopausal women (5-mg dose daily or a 35-mg dose once weekly); treatment of osteoporosis in post- menopausal women (10-mg daily dose or a 70-mg once-weekly dose); treatment of Paget’s disease of bone in men and women (40-mg dose); treatment and prevention of corti- costeroid-induced osteoporosis in men and women (5-mg dose); and treatment to increase bone mass in men (10-mg dose) Treatment of postmenopausal osteoporosis in women more than 5 years postmenopause with low Bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated Indications Merck Novartis Manufacturer Alendronate sodium Calcitonin-salmon Generic name Fosamax Tablets MIACALCIC Nasal Spray Product
Side effects include abdominal pain (6.6% vs 4.8% with placebo) and bone, muscle, or joint pain (4.1% vs 2.5% with placebo) Safety concerns include esophagitis, esophageal erosions, esophageal ulcers, oropharyngeal ulceration, and gastric or duodenal ulcers Well tolerated Side effects include rhinitis (12.0% vs 6.9% with placebo) and other nasal symptoms (10.6% vs 16.0% with placebo) Rare potential for systemic allergic reaction Safety/side effects 5 - or 10-mg tablet once per day 35-mg tablet once daily 40-mg tablet once daily (paget’s disease) 70-mg tablet once a week Must be taken at least 30 minutes bedore first food, drink, or medication of the day Must be taken with a 6-8 oz glass of plain water only After taking emdication, patient must remain upright for 30 mintues and until after her first food of the day Adequate calcium and vitamin D intake recommende 200 IU admisntered intranasally; one spray, once a day in alternate nostrils Adequate calcium and vitamin D intake recommended Dosing Fosamax Tablets MIACALCIC Nasal Spray Product
The use of Fosamax and Actonel results in long-term integration of bisphosphonates in the bone, with a half-life exceeding 10 years.
The consequences of this long-term retention of Fosamax and Actonel are unknown.
The safety of calcitonin-salmon has been established over a longer period of time than alendronate and risedronate.
Calcitonin-salmon has been used for 20 years worldwide; the first reported use of alendronate was in the early 1990s while the first reported use of risedronate was in the late 1990s.
MIACALCIC Nasal Spray & Actonel
Stops bone loss; helps build bone mass; reduces risk of fractures (vertebral and wrist) Stops bone loss; helps build bone mass Efficacy Prevention and treatment of osteoporosis in postmenopausal women (5-mg dose); gluccocorticoid-induced osteoporosis in postmenopausal women (5-mg dose); treatment of Paget’s disease of bone (30-mg dose) Treatment of postmenopausal osteoporosis in women more that 5 years postmenopause with low bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated. Indications risedronate sodium calcitonin-salmon Generic name Procter & Gamble, Aventis (co-marketeis) Novartis Manufacturer Actonel Tablets MIACALCIC Nasal Spray Product
Raloxifene has shifted its original position as a “designer estrogen” that provides the benefits of HRT without the risk of breast and endometrial cancer to a treatment and prevention therapy for osteoporosis with “proven protection and tolerability.”
This position is similar to our message of effective therapy that is convenient, well tolerated, and allows patients to lead an independent lifestyle
Raloxifene’s protection message doesn’t ring true for many patients who find it difficult to tolerate menopausal symptoms such as hot flashes and leg cramps.
Also, it can’t protect patients who may be at risk of thromboembolic events—particularly those who are inactive or live in an LTC facility.
With more than 20 years of documented safety, MIACALCIC Nasal Spray proves to be the appropriate choice for physicians who are looking for an effective, well-tolerated treatment option for women with postmenopausal osteoporosis.
Comparison of MIACALCIC Nasal Spray and Evista
60-mg tablet once per day
Must move about periodically during prolonged immobility
Adequate calcium and vitamin D intake recommended
200 IU administered intranasally; one spray, once a day, in alternate nostrils
Adequate calcium and vitamin D intake recommended
Safely concerns include prolonged restrictive movement due to increased risk of thromboembolic events (3.1 times higher in raloxifene group vs placebo group)
Side effects include rhinitis (12.0% vs 6.9% with placebo) and other nasal symptoms (10.6% vs 16.0% with placebo)
Rare potential for systemic allergic reaction
Stops bone loss; helps build bone mass; reduces risk of fractures (vertebral, ankle)
Stops bone loss; helps build bone mass
Efficacy Prevention and treatment of osteoporosis in postmenopausal women (60-mg dose) Treatment of postmenopausal osteoporosis in women more than 5 years postmenopause with low bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated Indications raloxifene hydrochloride calcitonin-salmon Generic name Eli Lilly Novartis Manufacturer Evista Tablets MIACALCIC Nasal Spray Product