Alendronate and Risedronate for the Treatment of Postmenopausal Osteoporosis: Clinical Profiles of the Once-Weekly and Once-Daily Dosing Formulations

Ronald Emkey, MD

Abstract and Introduction

Objective: The objective of this review is to present the clinical profiles of the once-weekly and once-daily dosing formulations of alendronate and risedronate, the 2 bisphosphonates currently available in the United States for the prevention and treatment of postmenopausal osteoporosis.
Data Source/Study Selection: Data were obtained from a MEDLINE literature search of all English language articles published between January 1996 and April 2004 using generic names of the bisphosphonates alendronate and risedronate. Results were refined by incorporating terms such as "osteoporosis," "bone mineral density," "fracture risk," and "adverse events." Randomized, controlled trials of once-daily and once-weekly bisphosphonate therapies were selected. Also selected for review were post hoc analyses and extension studies of the original controlled trials, including more recent data from published abstracts from scientific meetings.
Data Extraction: Relevant portions of articles obtained from the literature search were used to summarize the efficacy and tolerability of the 2 therapies.
Conclusions: In prospective trials, both bisphosphonates were effective in reducing vertebral and hip fractures in women with postmenopausal osteoporosis. In the only prospective trial evaluating hip fracture risk reduction as the primary end point, risedronate was effective at reducing hip fracture vs placebo. Both alendronate and risedronate are available in once-weekly formulations that have efficacy and tolerability profiles similar to the once-daily doses. Clinicians should review all available data for both agents as well as the medical history of the patient to make the most appropriate treatment choice.

Osteoporosis is characterized by low bone mass and a disruption in skeletal microarchitecture.^[1] The disease typically progresses without symptoms until a fracture occurs and has, therefore, been labeled a silent disease. Osteoporosis and low bone mass are estimated to be health concerns for more than 50% of people aged 50 years and older in the United States.^[1] Of the affected population, almost 70% are women with postmenopausal osteoporosis.^[1]

Fracture is the most serious clinical consequence of osteoporosis. Vertebral fracture can lead to significant back pain, disability, disfigurement, decreased quality of life, and an increased mortality rate.^[2,3] Moreover, women with at least 1 vertebral fracture have a 1 in 5 chance of sustaining another vertebral fracture within the following year, demonstrating the characteristic rapid progression of osteoporosis.^[4] Fractures of the wrist and humerus are also associated with disability.^[5] Moreover, all fractures, including fractures of the wrist, increase the risk of future fractures.^[6]

Hip fracture commonly results in profound physical disability, a need for short- or long-term nursing care, and loss of independence.^[7] One quarter of patients aged 50 years and older who fracture their hip die in the year following their fracture,^[8] and another 25% who were ambulatory before the hip fracture require long-term care afterward.^[9] Therefore, reduction of fracture risk is the most important goal of treatment for osteoporosis.

Because osteoporosis can be asymptomatic, compliance and persistence with medication dosing are not optimal. Poor daily compliance and lack of persistence are major issues for most patients with chronic asymptomatic diseases.^[10,11,12] Another potential detriment to compliance is the dosing regimen; that is, inflexible daily dosing schedules. For the bisphosphonates alendronate and risedronate, which are considered to be 2 of the most effective therapies for osteoporosis, this includes having to take the medication 30 minutes before the first meal or beverage other than water while remaining in an upright position.

Medications for the treatment of postmenopausal osteoporosis in the United States include the bisphosphonates alendronate, risedronate, and ibandronate; the selective estrogen receptor modulator raloxifene; salmon calcitonin nasal spray; and teriparatide. Alendronate, risedronate, and raloxifene are also approved for the prevention of postmenopausal osteoporosis, as well as various estrogen (Premarin, Alora, Climara) and estrogen plus progestin (Prempro, femhrt, Prefest, Vivelle) preparations. Although it is approved by the US Food and Drug Administration for the prevention and treatment of postmenopausal osteoporosis, ibandronate is not marketed in the United States. Only alendronate and risedronate are available in daily and once-weekly formulations.^[13,14] Raloxifene, salmon calcitonin, and teriparatide are currently available only in the daily formulation.^[15,16,17] Administration of hormone therapy may be once daily^{[18,19,20,21]} or continuous (transdermal).^[22,23,24]

In this article, the clinical profiles of the once-weekly and once-daily dosing formulations of alendronate and risedronate are reviewed. Data discussed are from a MEDLINE literature search conducted using the generic names of the bisphosphonates alendronate and risedronate. English language articles published between January 1996 and April 2004 were included. Terms such as "osteoporosis," "bone mineral density," "fracture risk," and "adverse events" were added to further refine the search results. All placebo-controlled trials evaluating once-daily alendronate and risedronate for postmenopausal osteoporosis were included in this review, with an emphasis on those studies that included fracture end points. Studies evaluating the once-weekly regimens included head-to-head comparisons with the once-daily regimens. Data from post hoc analyses of the pivotal trials and long-term extensions were also discussed, including data obtained from published abstracts from recent scientific meetings. The patients evaluated in these studies were predominantly white postmenopausal women. Data pertaining to other ethnic groups were not available.

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Cite this: Alendronate and Risedronate for the Treatment of Postmenopausal Osteoporosis: Clinical Profiles of the Once-Weekly and Once-Daily Dosing Formulations - Medscape - Jul 19, 2004.

Antifracture Results From Once-Daily Clinical Trials of Bisphosphonates in Postmenopausal Women With Osteoporosis
Reference	N	Treatment Duration	Fracture Relative Risk Reduction vs Placebo		Absolute Risk Reduction
Reference	N	Treatment Duration	Vertebral	Nonvertebral	Vertebral	Nonvertebral
Risedronate
VERT-NA^[34]	2458	1 year	65% (P < .001)	NA	4%
VERT-NA^[34]	2458	3 years	41% (P = .003)	39% (P = .02)	5%	3.2%
VERT-MN^[33]	1226	1 year	61% (P = .001)	NA	7.4%
		3 years	49% (P < .001)	33% (P = .06)	10.9%	5.1%
		5 years	50% (P < .001)^*	37% (P = .022)^*
HIP Study^[35]	5445	3 years	NA	40% (P = .009)		1.3%
HIP Study^[35]	1703	3 years	NA	60% (P = .003)
Alendronate
FIT I^[25]	2027	3 years	47% (P < .001)	20% (P = .063)	7%	2.8%
FIT II^[26]	4272	4 years	44% (P < .002)	12% (P = .13)	1.7%
Alendronate Phase 3 Osteoporosis Treatment Study^[27]	994	3 years	48% (P = .03)	21% (P value not reported)	3%	2.2%

HIP = Hip Intervention Program; NA = not analyzed; VERT-MN and VERT-NA = Vertebral Efficacy With Risedronate Therapy-Multinational and -North American trials, respectively; FIT I = Fracture Intervention Trial, first arm of trial in which patients had at least 1 vertebral fracture at baseline; FIT II = Fracture Intervention Trial, second arm of trial in which patients had no vertebral fractures at baseline.
^*Data from Sorensen et al.^[38]
Hip fracture risk only.
Subset of women from the HIP trial with vertebral fractures at baseline.

World Health Organization Criteria for Diagnosis of Osteoporosis Based on Bone Mineral Density Measurement
Status	BMD Measurement	T-score
Normal	< 1 SD below normal reference mean	-1 or above
Osteopenia	1 to 2.5 SDs below normal reference mean	Between -1 and -2.5
Osteoporosis*	> 2.5 SDs below normal reference mean	-2.5 or below

BMD = bone mineral density; SD = standard deviation.
*Women with osteoporosis and 1 or more preexisting fractures are considered to have severe or "established" osteoporosis.

Antifracture Results From Once-Daily Clinical Trials of Bisphosphonates in Postmenopausal Women With Osteoporosis
Reference	N	Treatment Duration	Fracture Relative Risk Reduction vs Placebo		Absolute Risk Reduction
Reference	N	Treatment Duration	Vertebral	Nonvertebral	Vertebral	Nonvertebral
Risedronate
VERT-NA^[34]	2458	1 year	65% (P < .001)	NA	4%
VERT-NA^[34]	2458	3 years	41% (P = .003)	39% (P = .02)	5%	3.2%
VERT-MN^[33]	1226	1 year	61% (P = .001)	NA	7.4%
		3 years	49% (P < .001)	33% (P = .06)	10.9%	5.1%
		5 years	50% (P < .001)^*	37% (P = .022)^*
HIP Study^[35]	5445	3 years	NA	40% (P = .009)		1.3%
HIP Study^[35]	1703	3 years	NA	60% (P = .003)
Alendronate
FIT I^[25]	2027	3 years	47% (P < .001)	20% (P = .063)	7%	2.8%
FIT II^[26]	4272	4 years	44% (P < .002)	12% (P = .13)	1.7%
Alendronate Phase 3 Osteoporosis Treatment Study^[27]	994	3 years	48% (P = .03)	21% (P value not reported)	3%	2.2%

Antifracture Results From Once-Daily Clinical Trials of Bisphosphonates in Postmenopausal Women With Osteoporosis
Reference	N	Treatment Duration	Fracture Relative Risk Reduction vs Placebo		Absolute Risk Reduction
Reference	N	Treatment Duration	Vertebral	Nonvertebral	Vertebral	Nonvertebral
Risedronate
VERT-NA^[34]	2458	1 year	65% (P < .001)	NA	4%
VERT-NA^[34]	2458	3 years	41% (P = .003)	39% (P = .02)	5%	3.2%
VERT-MN^[33]	1226	1 year	61% (P = .001)	NA	7.4%
		3 years	49% (P < .001)	33% (P = .06)	10.9%	5.1%
		5 years	50% (P < .001)^*	37% (P = .022)^*
HIP Study^[35]	5445	3 years	NA	40% (P = .009)		1.3%
HIP Study^[35]	1703	3 years	NA	60% (P = .003)
Alendronate
FIT I^[25]	2027	3 years	47% (P < .001)	20% (P = .063)	7%	2.8%
FIT II^[26]	4272	4 years	44% (P < .002)	12% (P = .13)	1.7%
Alendronate Phase 3 Osteoporosis Treatment Study^[27]	994	3 years	48% (P = .03)	21% (P value not reported)	3%	2.2%

Antifracture Results From Once-Daily Clinical Trials of Bisphosphonates in Postmenopausal Women With Osteoporosis
Reference	N	Treatment Duration	Fracture Relative Risk Reduction vs Placebo		Absolute Risk Reduction
Reference	N	Treatment Duration	Vertebral	Nonvertebral	Vertebral	Nonvertebral
Risedronate
VERT-NA^[34]	2458	1 year	65% (P < .001)	NA	4%
VERT-NA^[34]	2458	3 years	41% (P = .003)	39% (P = .02)	5%	3.2%
VERT-MN^[33]	1226	1 year	61% (P = .001)	NA	7.4%
		3 years	49% (P < .001)	33% (P = .06)	10.9%	5.1%
		5 years	50% (P < .001)^*	37% (P = .022)^*
HIP Study^[35]	5445	3 years	NA	40% (P = .009)		1.3%
HIP Study^[35]	1703	3 years	NA	60% (P = .003)
Alendronate
FIT I^[25]	2027	3 years	47% (P < .001)	20% (P = .063)	7%	2.8%
FIT II^[26]	4272	4 years	44% (P < .002)	12% (P = .13)	1.7%
Alendronate Phase 3 Osteoporosis Treatment Study^[27]	994	3 years	48% (P = .03)	21% (P value not reported)	3%	2.2%

Efficacy of Alendronate Once Weekly Compared With Alendronate Once Daily in Postmenopausal Women ^[41]
Efficacy Parameter (Assessment Time)	Alendronate Dosage
	10 mg daily (n = 370)	35 mg twice weekly (n = 369)	70 mg weekly (n = 519)
BMD, increase from baseline:
Lumbar spine (24 months)	7.4%^*	7.0%^*	6.8%^*
Bone turnover markers, decrease from baseline:
NTX/creatinine ratio (24 months)	74.9%^*	71.3%^*	73.4%^*
Mean BAP levels (24 months)	43.1%^*	41.7%^*	40.1%^*

BAP = serum bone-specific alkaline phosphatase; BMD = bone mineral density; NTX = urinary N-terminal telopeptide cross-linked type I collagen.
*P ≤ .001 vs baseline.

Efficacy of Risedronate Once Weekly Compared With Risedronate Once Daily in Postmenopausal Women ^[43]
Efficacy Parameter (Assessment Time)	Risedronate Dosage
	5 mg daily (n = 480)	35 mg weekly (n = 485)	50 mg weekly (n = 491)
BMD, increase from baseline:
Lumbar spine (12 months)	4.00%^*	3.94%^*	4.25%^*
Bone turnover markers, decrease from baseline:
NTX/creatinine ratio (12 months)	60.3%^*	60.7%^*	64.9%^*
Mean BAP levels (12 months)	42.4%^*	41.0%^*	45.7%^*

BAP = serum bone-specific alkaline phosphatase; BMD = bone mineral density; NTX = urinary N-terminal telopeptide cross-linked type I collagen.
*P < .05 vs baseline.
Met the criteria for noninferiority to the 5-mg once-daily risedronate regimen, defined as 95% upper confidence bound of the between-group difference of < 1.5%.
Not statistically different from the once-daily regimen based on 2-sided 95% confidence intervals for the treatment differences.^[43]

Drugs Approved in the United States for Management of Postmenopausal Osteoporosis
Treatment	Dosage	US FDA-Approved Indications	Approximate Pharmacy Cost for Monthly Treatment*
Risedronate	5 mg PO daily, 35 mg PO weekly	PMO, treatment	$75.53 $70.49
Risedronate	5 mg PO daily, 35 mg PO weekly	PMO, prevention	$75.53 $70.49
Alendronate	10 mg PO daily, 70 mg PO weekly	PMO, treatment	$75.40 $70.38
Alendronate	5 mg PO daily, 35 mg PO weekly	PMO, prevention	$75.40 $70.38
Estrogen	0.625 mg PO daily	PMO, prevention	$39.46
Raloxifene	60 mg PO daily	PMO, prevention	$81.52
Raloxifene	60 mg PO daily	PMO, treatment	$81.52
Calcitonin	200 IU daily intranasally	PMO, treatment	$86.43
Teriparatide	250 mcg/mL, subcutaneously	PMO, treatment	$599.20

FDA = Food and Drug Administration; PMO = postmenopausal osteoporosis; PO = by mouth.
*Costs based on 2004 average wholesale price.^[57]
Prempro (Wyeth Pharmaceuticals, Inc.)

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