Therapeutics and Clinical Risk Management
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`C o M Me nT aR y
`
`eliminating the need for fasting with oral
`administration of bisphosphonates
`
`Michael Pazianas1
`Bo abrahamsen 2,3
`Serge Ferrari4
`R Graham G Russell1,5
`1The Botnar Research Center and
`oxford University Institute of
`Musculoskeletal Sciences, oxford,
`UK; 2Department of Medicine F,
`Gentofte Hospital, Hellerup, 3odense
`Patient data explorative network
`(oP en) Institute of Clinical Research,
`University of Southern Denmark,
`odense, Denmark; 4Division of
`Bone Diseases, Faculty of Medicine,
`Geneva University Hospital, Geneva,
`Switzerland; 5Mellanby Centre for
`Bone Research, University of Sheffield,
`Sheffield, UK
`
`Correspondence: Michael Pazianas
`The Botnar Research Centre and
`oxford University Institute of
`Musculoskeletal Sciences, Nuffield
`Department of orthopaedics,
`Rheumatology and Musculoskeletal
`Diseases, Nuffield Orthopaedic Centre,
`Headington, oxford oX3 7LD, UK
`Tel +44 1865 227 335
`Fax +44 1865 227 966
`email michael.pazianas@ndorms.ox.ac.uk
`
`Abstract: Bisphosphonates are the major treatment of choice for osteoporosis, given that they
`are attached preferentially by bone and significantly reduce the risk of fractures. Oral bisphos-
`phonates are poorly absorbed (usually less than 1% for nitrogen-containing bisphosphonates) and
`when taken with food or beverages create complexes that cannot be absorbed. For this reason,
`they must be taken on an empty stomach, and a period of up to 2 hours must elapse before the
`consumption of any food or drink other than plain water. This routine is not only inconvenient
`but can lead to discontinuation of treatment, and when mistakenly taken with food, may result
`in misdiagnosis of resistance to or failure of treatment. The development of an enteric-coated
`delayed-release formulation of risedronate with the addition of the calcium chelator, ethylene-
`diaminetetraacetic acid (EDTA), a widely used food stabilizer, eliminates the need for fasting
`without affecting the bioavailability of risedronate or its efficacy.
`Keywords: bisphosphonates, osteoporosis treatment, absorption, EDTA, osteoclasts
`
`Introduction
`Bone loss resulting from unbalanced bone remodeling that favors bone resorption is
`a major feature of common bone pathologies, such as osteoporosis, Paget’s disease,
`and metastatic bone disease. In most cases, antiresorptive treatment helps to lower
`excessive resorptive activity to a level that better equates to bone formation and thus
`reduces the risk of fractures. Bisphosphonates are among the most effective and
`widely used antiresorptive agents available.1 An important and unique advantage of
`bisphosphonates is their selective uptake by the skeleton, coupled with preferential
`targeting of sites with increased bone activity. Oral formulations, however, are poorly
`absorbed (on average usually less than 1%), and concomitant intake of food or bever-
`age further limits absorption. For this reason, patients treated with oral bisphospho-
`nates are advised to refrain from oral intake (other than plain water) for up to 2 hours
`following administration of medication. However, it has been found that more than
`half of patients may ignore these directives.2
`The overall low oral bioavailability of bisphosphonates, together with the incon-
`venient routine of keeping the stomach empty for a considerable amount of time, led
`to the development and success of weekly and monthly regimens, and now to the
`development of a once-weekly regimen utilizing risedronate 35 mg delayed-release
`(DR), to which the well known chelating compound ethylenediaminetetraacetic acid
`(EDTA) has been added. This allows patients the option to take the tablet before or
`following a meal. This regimen has been approved in the US for administration after
`a meal as a new drug (due to the addition of EDTA) under the brand name Atelvia®,
`
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`Pazianas et al
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`and in Canada as Actonel DR®, whilst in Australia it has
`been licensed as Actonel EC® (enteric-coated tablets) for
`administration before and after breakfast.
`
`Structure and pharmacology
`of bisphosphonates
`Bisphosphonates are chemical compounds with a high affin-
`ity for bone mineral and therefore bind tightly to the exposed
`mineral surfaces of bone. At sites of bone formation, the newly
`deposited bisphosphonate becomes buried when additional
`bone is deposited on top. During the process of bone resorption,
`osteoclasts on the bone surface release acid and enzymes that
`resorb the mineralized matrix. In bisphosphonate-coated bone,
`osteoclasts encounter the chemical compound and ingest it,
`leading to their inactivation and possible death by apoptosis.3
`Bisphosphonates are modified analogs of inorganic
`pyrophosphate structures where the oxygen connecting the
`two phosphate groups (P-O-P) is replaced by a carbon atom
`(P-C-P), as shown in Figure 1.4 As a result, bisphospho-
`nates are resistant to chemical and enzymatic degradation.
`
`The addition of nitrogen in their structure (N-BPs) enhances
`their binding affinity and antiresorptive potency. Non-N-BPs,
`such as tiludronate, are little used today, whereas etidronate
`and clodronate are still sometimes prescribed to patients with
`osteoporosis or metastatic bone disease, respectively. The
`N-BPs in oral (alendronate, risedronate, ibandronate) or par-
`enteral (intravenous) preparations (ibandronate, pamidronate,
`and zoledronate) act on the same pathway, ie, the mevalonate
`pathway, as the cholesterol-lowering drugs (statins) albeit
`downstream (Figure 2).4 They inhibit the farnesyl pyrophos-
`phate synthase enzyme, thereby preventing prenylation (lipid
`modification) of many small GTPases, such as Ras, Rab, Rho,
`and Rac, a large group of signaling proteins that are critical
`for the function and survival of osteoclasts.3
`
`Bisphosphonates
`reaching osteoclasts
`enteric absorption of bisphosphonates
`Oral formulations, especially the N-BPs, are poorly absorbed
`(∼1%)5 and their bioavailability may be negligible if taken
`
`Both phosphonate groups act as a
`‘bone hook’ and are essential both for
`binding to hydroxyapatite (HAP) and
`within the Farnesyl Pyrophosphate
`Synthase (FPPS) enzyme
`
`OH
`
`OH
`
`OH
`
`OH
`
`R1
`
`P
`
`C
`
`P
`
`...........
`Mg
`
`Mg
`..........
`
`OH
`
`R2N
`
`C=O
`
`O
`II
`
`P P
`
`II
`O
`
`R1 is an OH group that
`binds to bone via Ca2+
`
`R2 group determines
`anti-resorptive potency
`and affects binding to
`HAP
`
`R2N
`
`Mineral Affinity
`depends on
`N-H-OH angle
`
`R1
`
`R2
`
`C
`
`R1
`
`P
`
`C
`P
`
`X°
`
`OH
`
`Ca
`
`HAP
`
`Bone surface
`
`N-O distance
`determines strength of binding
`
`FPPS enzyme
`
`Bone mineral binding
`
`Biochemical mechanism
`
`Figure 1 Bisphosphonate structure, bone mineral binding, and biochemical mechanisms.
`Note: Reproduced from Pazianas M, Compston J, Huang CL-H. Atrial fibrillation and bispho sphonate therapy. J Bone Miner Res. 2010;25:2–10.4 With permission of the
`american Society for Bone and Mineral Research.
`
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`eliminating fasting with oral administration of bisphosphonates
`
`Osteoclast
`
`N-bisphosphonates
`
`Isoprenylation of proteins
`
`HMG Co-A
`
`Mevalonate
`
`Farnesyl-PP
`
`Geranylgeranyl-PP
`
`Squalene
`
`Cholesterol
`
`Liver
`
`Statins
`
`O
`
`O
`
`O
`
`H
`
`H3C
`
`H3C
`
`O
`
`CH3
`
`H
`
`H
`
`CH
`
`H3C
`
`Bone resorption inhibited
`
`Cholesterol synthesis inhibited
`
`Figure 2 Inhibition of the mevalonate pathway by statins and bisphosphonates.
`Note: Reproduced from Pazianas M, Compston J, Huang CL-H. Atrial fibrillation and bispho sphonate therapy. J Bone Miner Res. 2010;25:2–10.4 With permission of the
`american Society for Bone and Mineral Research.
`Abbreviation: HMG Co-a, 3-hydroxy-3-methylglutarylcoenzyme a.
`
`on a full stomach. This may be due to the formation of
`insoluble chelates with elements such as calcium, magne-
`sium, and aluminum, which are naturally present in many
`foods and liquids, but other mechanisms may be important.
`For these reasons, bisphosphonates must be taken before
`breakfast, with no subsequent food/beverage intake for at
`least 30 minutes and often longer. At the other end of the
`spectrum, commonly used medications such as proton pump
`inhibitors, which work by reducing the secretion of gastric
`acid, effectively elevate gastric pH, and may have the effect of
`increasing bisphosphonate bioavailability.6,7 Although some
`non-N-BPs can be metabolized intracellularly to cytotoxic
`adenosine triphosphate analogs, in general bisphos phonates
`are excreted in the urine unmetabolized. Moderate or severe
`renal impairment therefore may increase plasma concentra-
`tions, and their use is not recommended in patients with
`creatinine clearance less than 30 mL per minute.
`Our current understanding is that bisphosphonates are
`likely to be absorbed throughout the intestine, although
`more effectively in segments with comparatively larger
`surface areas (jejunum .duodenum .ileum).8 Studies
`using pamidronate and tiludronate on human intestinal
`
`epithelial CaCo-2 cells9,10 and alendronate in a rat model8
`suggest that bisphosphonates find their way into the systemic
`circulation through the paracellular and not the transcel-
`lular route (Figure 3). More specifically, bisphosphonates
`reach the bloodstream through the tight junctions connect-
`ing epithelial cells and pores permeable to molecules up
`to a molecular weight of 150. Bisphosphonates, however,
`are in the 200–400 molecular weight range, which limits
`
`Tight junction
`
`Apical
`membrane
`
`Paracellular pathway
`
`Transcellular pathway
`
`Basolateral membrane
`
`Figure 3 Paracellular, transcellular route, and tight junctions.
`
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`Pazianas et al
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`effective absorption.11,12 Additionally, divalent ions, such
`as calcium and magnesium, are crucial for the function of
`tight junctions. Divalent cations bind strongly to all bispho-
`sphonates, including N-BPs, and form chelates. Further, the
`lack of transcellular crossing coupled with the considerable
`hydrophobicity of the lining of the small intestine (and gastric
`and colonic mucosa) serves as a further limiting factor to the
`absorption of hydrophilic oral N-BPs, such as alendronate
`and risedronate.
`
`Bisphosphonate uptake by osteoclasts
`Osteoclasts ingest bisphosphonates via fluid phase endocy-
`tosis, while two other modes of uptake, ie, adsorptive and
`receptor-mediated endocytosis, are probably not involved.13
`This fluid phase endocytosis is a low-efficiency and nonspe-
`cific process characterized by bulk uptake of solutes in exact
`proportion to their concentration in extracellular fluid.14
`
`Fasting and its effects on adherence
`(persistence/compliance)
`Using the concepts of persistence (how long a patient contin-
`ues therapy), compliance (how correctly, in terms of dose and
`frequency, a patient takes the medication), and adherence (a
`combination of persistence and compliance),15 it is possible
`to quantify their impact on treatment outcomes. Generally, the
`adherence rate for prescribed medications could be as low as
`0%, with an average of 50% for medications used in several
`chronic diseases.16 Low adherence could be mischaracterized
`
`as treatment failure and could lead to unnecessary and poten-
`tially harmful treatment modifications.17
`Interestingly, improving adherence does not increase the
`incidence of adverse events.18 In the case of osteoporosis,
`where the condition is asymptomatic and medication is taken
`primarily to prevent long-term skeletal complications, it has
`been estimated that one third to one half of patients do not
`take their medication as directed, and nonadherence may
`begin soon after treatment initiation.15 Even in countries
`reporting relatively good persistence with osteoporosis
`treatment, the mean persistence on oral bisphosphonates is
`only about 3 years.19
`Treatment response is related to the dosage and admin-
`istration of a therapy. The need to fast has been identified
`among the top three issues reported by patients as the reason
`for poor adherence20 (Figure 4). The inconvenience is obvious
`because overnight fasting prior to taking the medication and
`continuing for up to 2 hours afterwards could severely disrupt
`daily routines. Therefore, development of a formulation that
`would allow the patient to take the medication following
`breakfast is expected to improve adherence.21
`Overcoming the fasting hurdle
`Prevention of bisphosphonates from forming insoluble
`complexes with calcium and other divalent or trivalent
`cations present in food was found to be key to overcoming
`the fasting requirement. Therefore, use of chelating agents
`such as EDTA, which is commonly used as an antidote to
`
`Dislike long-term medication
`
`Frequency of taking
`
`I
`
`Inconvenience
`
`Not feeling it works
`
`Remembering to take
`
`Fasting
`
`Side effects
`
`Staying upright
`
`I
`
`I
`
`I
`
`0
`
`I
`
`5
`
`I
`
`10
`
`I
`
`15
`
`%
`
`I
`
`I
`
`20
`
`25
`
`Figure 4 Fasting has been identified as one of the three main reasons for discontinuing treatment.
`Note: Reproduced with permission from International osteoporosis Foundation. The adherence gap: why osteoporosis patients don’t continue with treatment.20
`
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`eliminating fasting with oral administration of bisphosphonates
`
`metal toxicity22 in humans and extensively as a preservative
`in foods,23 has been explored.
`Like bisphosphonates, chelating agents such as EDTA are
`poorly absorbed. Of orally consumed EDTA, for example,
`only 5% or less is absorbed and is almost entirely excreted
`unchanged in the urine (95%) within 72 hours.24 The low
`bioavailability of EDTA, however, becomes advantageous
`when a local but not systemic effect is desired. Indeed, coad-
`ministration of EDTA with an oral bisphosphonate could
`ensure that calcium and other divalent or trivalent cations
`present in the food would be preferentially bound by the
`chelating agent and not by the bisphosphonate.
`Furthermore, EDTA could enhance permeability by acting
`as a chelator of tight junction calcium ions, thereby widening
`the paracellular tight junctions, resulting in better absorption of
`bisphosphonate. This concept was tested in the early 1990s.25
`Alendronate or clodronate were given subcutaneously or by
`mouth together with EDTA in aqueous solution at neutral pH
`in a rat model of hypercalcemia. Absorption was increased by
`about ten-fold in animals treated with 0.6 mg/kg alendronate
`and decreased to two-fold with lower doses. The minimal
`effective dose for EDTA was estimated at 10 mg/kg for the
`alendronate-treated animals and 100 mg/kg for those treated with
`clodronate. However, the amount of EDTA required to achieve
`these increases was deemed clinically unacceptable.25
`Today, we are able to use amounts of EDTA that are effec-
`tive and clinically safe following the development of a tablet
`that protects the drug from gastric release and allows relatively
`rapid release in the small intestine (pH .5.5), where the con-
`centrations of calcium and other divalent or trivalent cations
`are anticipated to be lower than in the fed stomach. Therefore,
`the amount of EDTA required to bind free cations present in
`the region of drug release should be less. This advance led to
`the development of an oral, once-weekly 35 mg risedronate
`DR formulation with a pH trigger of 5.5, combined with
`100 mg EDTA. The lag time (time for initial tablet opening)
`is usually 10 minutes and not more than 15 minutes. Dissolu-
`tion is mostly complete (.95%) at 45 minutes. The coating
`of the tablet withstands prolonged exposure (16 hours) up to
`pH 5.0, thus preventing premature release in the stomach in
`cases of prolonged gastric retention and/or increased gastric
`pH. Further, the disintegration time is 4–12 times longer for
`the DR tablet than for the immediate-release (IR) tablet, and
`thus the potential would be less for disintegration of the DR
`tablet within the esophagus, where the environment is neutral,
`if transit time is delayed leading to esophageal exposure to
`risedronate. In this new formulation, the bioavailability of the
`risedronate 35 mg DR tablet is not markedly affected by the
`
`type of food administered at breakfast (typical or high-fat).
`The time to peak concentration for the 35 mg risedronate DR
`formulation tablet is ∼3 hours when administered in the morn-
`ing 4 hours prior to a meal. Its bioavailability is decreased
`by ∼30% when administered after a high-fat breakfast, but
`is still similar or 2–4-fold greater when compared with the
`35 mg IR tablet administered 30 minutes prior to a high-fat
`breakfast. It is worth adding that when both formulations
`were administered after an overnight fast and followed by a
`4-hour fast, systemic exposure for the 35 mg DR formulation
`was approximately 44% greater than that for the 35 mg IR
`formulation (data on file, Procter & Gamble, 2009).
`Plasma protein binding of risedronate in humans averages
`about 24%. Approximately 60% of the dose is distributed to
`bone and the remainder of the dose is excreted in the urine.
`The renal clearance is not concentration-dependent, and there
`is a linear relationship between renal and creatinine clearance.
`The renal clearance of risedronate was decreased by about
`70% in patients with a creatinine clearance of approximately
`30 mL per minute as compared with persons with normal
`renal function. The 35 mg risedronate DR formulation is not
`recommended for use in patients with severe renal impair-
`ment (creatinine clearance less than 30 mL per minute),
`but no dose adjustment is necessary for higher creatinine
`clearances. Also, dosage adjustment is unlikely to be needed
`in patients with hepatic impairment. Unabsorbed drug is
`eliminated unchanged in feces.26
`The risedronate 35 mg DR once-weekly tablet also con-
`tains 100 mg EDTA. This is less than the acceptable daily
`intake (2.5 mg/kg as the calcium, disodium salt, which equates
`to 149 mg/day for a 60 kg person). It is expected to sequester
`a relatively small amount of calcium (approximately 10 mg)
`from the gastrointestinal tract. There is also no impact on
`solubility, and hence the absorption of coadministered drugs.
`Further, in patients treated with risedronate 35 mg DR imme-
`diately following a standard meal and a proton pump inhibitor
`such as omeprazole or 600 mg calcium/400 IU vitamin D
`supplement, the bioavailability of risedronate was similar to
`that of the 35 mg IR tablet given at least 30 minutes before
`breakfast (data on file, Procter & Gamble, 2009). However,
`gastric acid-suppressive agents (antacids), calcium supple-
`ments, magnesium-based supplements or laxatives, and iron
`preparations should be taken at a different time of the day.26
`
`Clinical data: once a week
`risedronate 35 mg DR
`A randomized, double-blind, active-controlled, parallel-
`group study assessed the safety and efficacy of risedronate
`
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`Total proximal femur
`
`**
`
`*
`
`Week 26
`
`Week 52
`Visit
`
`Week 104
`
`Endpoint
`
`Femoral trochanter
`
`**
`
`**
`I
`I
`
`Week 26
`
`Week 52
`Visit
`
`Week 104
`
`Endpoint
`
`6 5 4 3 2 1 0
`
`Mean percent change from
`
`baseline ± SE
`
`Baseline
`
`6 5 4 3 2 1 0
`
`Mean percent change from
`
`baseline ± SE
`
`Baseline
`
`Lumbar spine
`
`**
`
`_-...-
`
`Week 26
`
`Week 52
`Visit
`
`Week 104
`
`Endpoint
`
`Femoral neck
`
`*
`... I
`········::·::·.:.-;
`···::·---
`
`*
`
`*
`
`I
`
`Week 26
`
`Week 52
`Visit
`
`Week 104
`
`Endpoint
`
`6 5 4 3 2 1 0
`
`Pazianas et al
`
`A
`
`Mean percent change from
`
`baseline ± SE
`
`Baseline
`
`6 5 4 3 2 1 0
`
`Mean percent change from
`
`baseline ± SE
`
`Baseline
`
`Mean percent change from
`
`B
`
`Mean percent change from
`
`baseline ± SE
`
`−20
`
`−30
`
`−40
`
`−50
`
`•• -=--=-·!.!.,!..!..!!!..!-.::. ___ _ •
`
`−60
`Baseline Week 13 Week 26 Week 52
`Visit
`
`Week 104 Endpoint
`
`0
`
`−10
`
`Urine NTX/Cr
`
`0
`
`−10
`
`Serum CTX
`
`*
`
`----------i
`**
`
`•
`•
`**
`
`baseline ± SE
`
`−20
`
`−30
`
`−40
`
`−50
`
`*
`
`−60
`Baseline Week 13 Week 26 Week 52
`Visit
`
`Week 104 Endpoint
`
`I
`
`Week 104 Endpoint
`
`Serum BAP
`
`0
`
`−10
`
`baseline ± SE
`
`−20
`
`−30
`
`−40
`
`−50
`
`−60
`Baseline Week 13 Week 26 Week 52
`Visit
`
`Mean percent change from
`
`Figure 5 Mean percent change from baseline ± standard error of the mean in (A) bone mineral density and (B) bone turnover markers over 2 years in women receiving
`risedronate 5 mg immediate-release daily (solid lines with black circles), 35 mg delayed-release immediately following breakfast weekly (dashed lines with black squares), or
`35 mg delayed-release at least 30 minutes before breakfast weekly (circle dashed lines with black triangles). Asterisk represents statistically significant difference between
`immediate-release daily and delayed-release weekly treatment group.
`Note: With kind permission from Springer Science+Business Media: McClung MR, Balske a, Burgio De, Wenderoth D, Recker RR. Treatment of postmenopausal osteoporosis
`with delayed-release rise dronate 35 mg weekly for 2 years. Osteoporos Int. 2013;24:301–310.29
`Abbreviations: CTX, C-terminal telopeptide; Se, standard error of the mean; CR, creatinine; BaP, bone alkaline phosphatase.
`
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`eliminating fasting with oral administration of bisphosphonates
`
`35 mg DR weekly in a “noninferiority” test27 during the first
`year of a 2-year study.28 The “noninferiority” or “bridging”
`investigational approach has been used as a realistic substitute
`for mandatory antifracture studies involving approved daily
`oral bisphosphonate regimens when seeking approval for new
`intermittent administration (weekly or monthly regimens).
`The requirement in these cases has been bone mineral density
`(BMD) and bone turnover marker comparisons with the daily
`oral regimens and proof of “noninferior” outcomes. Fracture
`data are being collected as adverse effects.28
`In total, 767 postmenopausal osteoporotic women with
`lumbar spine or total hip BMD corresponding to a T-score
`of −2.5 or lower or a T-score of −2.0 or lower with at
`least one prevalent vertebral fracture (T4–L4) completed
`12 months of the study. They had been allocated to one
`of three groups, two of them treated with once-weekly
`risedronate 35 mg DR either at least 30 minutes before
`(delayed-response before breakfast [DRBB], n=258) or
`immediately following breakfast (delayed-response fol-
`lowing breakfast [DRFB], n=252) and the third one treated
`with the established regimen of 5 mg risedronate IR daily
`before breakfast (n=257) according to US Food and Drug
`Administration requirements.
`The percent change from baseline in lumbar spine BMD
`was the primary end point. At the end of year one, the mean
`percent changes (increase) in BMD and bone turnover mark-
`ers (decrease) were similar across groups. The occurrence
`of new incident morphometric vertebral fracture was very
`low and remarkably similar in the three groups. Overall, the
`efficacy of once-weekly risedronate 35 mg DR administered
`before or following breakfast was noninferior to that of rise-
`dronate 5 mg IR daily. The same pattern was observed in the
`adverse effects/tolerability profile of once-weekly risedronate
`35 mg DR, with no significant differences between groups.
`Participants dropped out of the study in similar proportions
`across treatment groups. This is not an unexpected finding
`in randomized controlled trials, and may not be interpreted
`as nonimproved adherence in the once-weekly risedronate
`35 mg DR group. The incidence of upper gastrointestinal
`adverse events (upper abdominal pain) in the DRBB group
`and lower gastrointestinal adverse events (mild to moder-
`ate diarrhea) in the DRFB group were numerically but not
`statistically higher. Small transient decreases in serum cal-
`cium provoking reciprocal changes in total PTH (1-84) were
`recorded in the first few weeks of treatment in the groups
`receiving DR-EDTA, but ran their course without causing
`any clinical symptomatology.
`A total of 722 participants completed 2 years of
`treatment.29 Both groups receiving weekly DR risedronate
`
`Therapeutics and Clinical Risk Management 2013:9
`
`demonstrated BMD increases at the lumbar spine and total
`hip similar to or greater than that with the risedronate 5 mg
`IR daily dose group (Figure 5A). Decreases in bone turnover
`markers were similar or significantly lower in the weekly
`risedronate DR groups (Figure 5B). The noninferiority
`of risedronate DR, further supported by bone histomorpho-
`metric data (the “gold standard” in assessing bone structure
`and function). After 2 years of treatment, bone-forming
`activity (presence of double tetracycline label) was evident
`in all 45 samples examined.
`Histomorphometric measurements (static and dynamic)
`and parameters of bone mineralization were similar across
`treatment groups. These findings are in line with those
`reported after 1, 3, and 5 years of treatment with 5 mg
`risedronate IR daily in postmenopausal women, providing
`assurance that the weekly 35 mg risedronate DR does not
`cause excessive reduction of bone turnover. In patients treated
`with other antiresorptive medications, such as alendronate or
`denosumab (antibody to RANK ligand), tetracycline labels
`have been hard to find in many subjects.30,31 Finally, new
`incident morphometric vertebral fractures were not signifi-
`cantly different between the DR and IR groups (five in the
`IR daily group, two in the DRFB weekly group, and six in
`the DRBB weekly group).
`
`Conclusion
`The DR formulation of risedronate has simplified the dosing
`regimen for bisphosphonates without compromising clinical
`efficacy, and probably improving it, based on BMD evidence.
`Avoiding the inconvenience of fasting should motivate
`osteoporotic patients to take their treatment for longer and
`therefore may improve poor adherence rates of bisphospho-
`nate use. Further studies are required to confirm this.
`
`Author contributions
`All authors made substantial contributions to the concep-
`tion, design, drafting, reading, and editing of this paper, and
`approved the final manuscript.
`
`Disclosure
`MP is a consultant to the Alliance for Better Bone Health
`and Warner Chilcott. BA serves on advisory boards for
`Nycomed and Amgen, and has received speakers fees from
`Nycomed, Eli Lilly, Amgen, and MSD, and has had research
`contracts with NPS Pharma, Amgen, and Novartis. SF has
`consulted and served on advisory boards for MSD, Amgen,
`GSK, Eli Lilly, Novartis, and Pfizer (Switzerland), has
`received research grants from MSD and Amgen, and lecture
`fees from MSD, Amgen, GSK, Eli Lilly, Novartis, Servier,
`
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`Pazianas et al
`
`Dovepress
`
`Sanofi, Warner Chilcott, Roche (Switzerland), and Pfizer.
`RGGR has received research support from Sanofi-Aventis
`and Warner Chilcott, and undertaken consultant/speaker and
`legal activities with Amgen, Chronos, GlaxoSmithKline,
`Roche, Procter and Gamble, Sanofi-Aventis, Novartis, Eli
`Lilly, and Warner Chilcott.
`
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