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Screening, diagnosis and treatment of osteoporosis:

a brief review

Roberto Bernabei sults in bone fragility and increased risk of fractures. Accord-
Anna Maria Martone ing to the World Health Organization (WHO), osteoporosis is
Elena Ortolani defined as a bone mineral density (BMD) at the hip and/or
Francesco Landi the spine at least 2.5 standard deviations below the mean
Emanuele Marzetti peak bone mass of young healthy adults as determined by
dual-energy X-ray absorptiometry (DXA) (1).
The prevalence of osteoporosis rises steadily with advancing
Department of Geriatrics, Neurosciences and Orthopedics, age and is projected to increase substantially due to the de-
Catholic University of the Sacred Heart School of Medicine, mographic transition occurring worldwide. Osteoporosis is
Rome, Italy estimated to cause 1.5 million fractures annually in the Unit-
ed States (2). In Italy, approximately 3.5 million persons are
osteoporotic, with over 90.000 fractures yearly in those aged
Address for correspondence: 50 years or older (3).
Emanuele Marzetti, MD, PhD Mortality associated with osteoporotic fractures ranges from
Department of Geriatrics, Neurosciences and Orthopedics 15 to 30%, a rate similar to breast cancer and stroke (3).
Catholic University of the Sacred Heart School of Medicine Furthermore, 50% of women with osteoporotic hip fractures
University Hospital “Agostino Gemelli” develop disability, with significant impact on the capacity to
Largo A. Gemelli 1 live independently and, in most cases, institutionalization (3).
00168 Rome, Italy Several risk factors have been identified for primary osteo-
Phone: +39 06 3015-5559 - Fax: +39 06 3051-911 porosis (Table 1). Secondary osteoporosis may be the con-
E-mail: sequence of endocrine and metabolism disorders (e.g., hy-
pogonadism, hypercortisolism, hyperparathyroidism, hyper-
thyroidism, anorexia), lymphoproliferative disorders, intesti-
Summary nal malabsorption conditions, rheumatoid arthritis, renal fail-
ure, collagenopathies, or certain drugs (e.g., corticosteroids,
Osteoporosis is a highly prevalent condition character- selective serotonin reuptake inhibitors, anticoagulants and
ized by decreases in bone mass and microarchitectural antidiabetic medications) (3). Regardless of the etiology, in
alterations. Bone fractures, especially of the hip and ver- all cases of osteoporosis an imbalance exists between bone
tebrae, are the most burdensome complications of osteo- resorption and formation: the rate of bone formation is often
porosis, being associated with high risk of disability, in- normal, whereas resorption by osteoclasts is increased (4).
stitutionalization and mortality. The detection of osteo- However, the initiating event in the process of osteoclastic
porosis relies on the quantification of bone mineral densi- activation is not yet completely understood.
ty via imaging techniques such as dual-energy X-ray ab-
sorptiometry. However, therapeutic decision-making
should be based on a comprehensive fracture risk as- Screening and diagnosis of osteoporosis
sessment, which may be obtained through validated algo-
rithms. Once the decision of treating has been taken, non- The presence of osteoporosis should be ascertained in all
pharmacological strategies should be implemented to- women aged ≥ 65 years (2). Men ≥ 65 years or women aged
gether with the prescription of anti-osteoporotic agents. ≤ 65 years should be screened for the presence of risk fac-
Numerous drugs are currently available to treat osteo- tors such as early menopause (≤ 45 years), anorexia, smok-
porosis and the choice of a specific compound should be ing habit or alcohol abuse, chronic use of certain drugs or
guided by efficacy and safety considerations. The present diseases associated with an increased risk for osteoporosis
review provides a concise synopsis of the current evi-
dence in the management of osteoporosis, from screen- Table 1 - Major risk factors for primary osteoporosis.
ing to drug prescription. Novel anti-osteoporotic agents
are also briefly presented. Advancing age
Female sex
KEY WORDS: vitamin D; denosumab; bisphosphonates; teriparatide; strontium White or Asian race
ranelate. Low body weight / body mass index
Family history of osteoporotic fractures
Early menopause
Introduction Sedentary lifestyle
Excessive alcohol (> 2 drinks per day), caffeine, and tobacco use
Low calcium and/or vitamin D intake
Osteoporosis is a bone disease characterized by a decrease
Inadequate sun exposure
in bone mass and microarchitectural alterations which re-

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R. Bernabei et al.

(3). The first-line assessment includes the determination of the diet, in particular blue fish and dairy products. The vita-
erythrocyte sedimentation rate, blood cell count, protein min D precursor is liposoluble and settles mostly in the adi-
electrophoresis, serum calcium, serum phosphorus, serum pose tissue. The free quota is converted in the liver into 25-
alkaline phosphatase, serum creatinine, and 24-hour urinary hydroxycolecalciferol [25 (OH) D], the major circulating vita-
calcium excretion, in order to exclude possible causes of min D metabolite, whose levels are the most reliable index of
secondary osteoporosis (3). Determination of bone turnover vitamin D status. 25 (OH) D is converted into the active
markers is not recommended. metabolite in the kidney, through a complex homeostatic
DXA is presently considered the gold standard imaging tech- mechanism involving parathyroid hormone (PTH) and calci-
nique for the diagnosis of osteoporosis because it shows the um and phosphorus serum levels (6).
best predictive value for fracture risk (3). An estimate of frac- Vitamin D receptors are ubiquitous and are especially abun-
ture risk may be obtained with DXA of radium, ulna, spinal dant in osteoblasts, chondrocytes, hepatocytes, parathyroid
column or proximal femur. In persons aged ≥ 65 years DXA cells, and muscle cells (6). Vitamin D promotes cell prolifera-
should be performed at the proximal femur because os- tion and differentiation by a genomic pathway (7, 8). Vitamin
teoarthritis of the column may bias the results. Moreover, D also acts via a non-genomic mechanism to modulate cell
BMD of the hip is a stronger predictor of future fracture risk responses to various stimuli (7, 8). The major actions of vita-
than spine BMD. As a general rule, the risk of fracture in- min D in the context of bone homeostasis include the regula-
creases 1.5-3 times each standard deviation of BMD below tion of calcium metabolism by increasing intestinal absorption
the reference population (3). Normal BMD is indicated by a T and renal reabsorption, and the stimulation of the synthesis of
score of 1 to -1, whilst a T score ≥ -2.5 is diagnostic for os- bone proteins such as osteocalcin by osteoblasts (9).
teoporosis. T score values between -1 and -2.5 identify a The daily vitamin D allowance ranges from 1,500 IU (healthy
condition known as osteopenia which is associated with low adults) to 2,300 IU (elderly with low calcium intake). Since
to medium fracture risk, but frequent progression to osteo- the average Mediterranean diet provides around 300 IU per
porosis. The correct identification and management of os- day, subjects with insufficient sun exposure should receive
teopenic subjects is a high-priority public health issue, if one 1,200-2,000 IU vitamin D daily (10-12).
considers that approximately 35 million Americans suffer In Italy, approximately 50% of young healthy individuals
from osteopenia (5). show vitamin D insufficiency [i.e., serum 25(OH)D levels 20-
The estimation of absolute risk of fractures and, therefore, 30 ng/mL] during the winter season (13). The prevalence of
therapeutic decision-making should not be based solely on vitamin D deficiency [i.e., serum 25(OH)D levels < 20 ng/mL]
BMD determination; rather, it requires a comprehensive eval- increases with advancing aging, affecting virtually all non-
uation of the patient, taking into account all of the known risk supplemented elderly subjects (14). As such, individuals
factors for osteoporotic fractures. In this context, sensitive aged 70 years or older should be considered vitamin D insuf-
tools have been developed which are routinely used in clini- ficient unless they pursue a lifestyle characterized by exten-
cal practice. Besides its role in the identification of osteo- sive sun exposure (15). It is therefore recommended to pre-
porosis, DXA is also useful to monitor the efficacy of specific scribe older adults with vitamin D supplementation (800 per
treatments. Roughly, 0.5-2% of bone mass is lost every year, day) as a primary prevention measure (Table 2) (15).
whilst anti-osteoporosis therapies allow gaining approximate- If vitamin D deficiency is detected, a cumulative dose of
ly 1-6% yearly. Since the least significant change of DXA is 300,000-1,000,000 IU over 1-4 weeks is recommended, fol-
2-4%, it is recommended to repeat it not earlier than 1-2 lowed by a maintenance dose of 800-2.000 IU/day (or week-
years from the beginning of treatment (3). ly/monthly equivalent) (15). The dosage should be based on
age, degree of sun exposure, and baseline 25(OH) D levels
(Table 2). In subjects persistently at risk for deficiency, it is
Therapeutic strategies against osteoporosis recommended to check vitamin D serum concentration after
3-6 months from the beginning of the supplementation regi-
Non-pharmacological treatments men (15). Finally, vitamin D supplementation should be care-
Many strategies are available to prevent osteoporosis and its fully monitored in patients at risk of vitamin D intoxication
complications, such as supplementation with calcium (500- (granulomatosis) or with primary hyperparathyroidism (15).
1,000 mg daily) and vitamin D, physical activity and multidis-
ciplinary interventions to decrease the risk of falls (5). These Physical activity
premises also represent the basis for every specific pharma- Physical activity is highly effective in attenuating the age-re-
cological treatment, since calcium and vitamin D deficiency lated bone mass loss (16, 17). It is therefore recommended
is the most common cause of non-responsiveness to anti-os- to carry out a minimum of activity (for example, 30 minutes
teoporotic medications. of walk daily) for its positive effects on bone mass and the
risk of falling (18).
Vitamin D supplementation
The major active metabolite of vitamin D, 1α,25-dihydroxy- Comprehensive interventions on the risk of falls
colecalciferol [1,25 (OH)2D3] derives for 80% from the con- Exercises for muscle strengthening and gait training have
version of 7-dehydrocholesterol by UV light and 20% from shown to reduce the risk of falls and related injuries in elder-

Table 2 - Vitamin D supplementation dosages.

Baseline 25 (OH)D levels Cumulative therapeutic dose of vitamin D Daily maintenance dose
<10 ng/mL or 25 nmol/L 1,000,000 2,000
10-20 ng/mL or 25-50 nmol/L 600,000 1,000
20-30 ng/mL or 50-75 nmol/L 300,000 800

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Screening, diagnosis and treatment of osteoporosis: a brief review

ly subjects (18). Psychotropic drugs (e.g., benzodiazepines, the probability of repeated stresses to the gastro-esophageal
antipsychotics, and antidepressant) should be avoided mucosa (23-28). Acute phase response (APR) is a transient
whenever possible or used with extreme caution. Adequate flu-like syndrome, usually lasting 2-3 days, that develops in
measures should finally be taken to avoid falls at home (e.g., 30% of patients after the first intravenous administration of
handrails on stairs and handholds in the bathroom). amino-bisphosphonates (29). It is associated with a rapid re-
duction of circulating lymphocites and increases in serum
Pharmacological treatments levels of C-reactive protein. APR can be prevented or man-
Treatment threshold aged with paracetamol or non-steroidal anti-inflammatory
BMD as estimated by DXA does not suffice to start an anti- drugs (30).
osteoporotic treatment. As previously mentioned, a compre- Atypical femoral subtrochanteric/diaphyseal fractures have
hensive assessment is necessary to quantify long-term frac- been described in patients under long-term biphosphonate
ture risk (18). In fact, pharmacological treatments are aimed treatment, particularly in those receiving glucocorticoids
at individuals who are already osteoporotic and therefore at and/or another anti-resorptive medication (31-35). Atypical
risk of osteoporotic fractures or re-fractures. femoral fractures develop spontaneously or after a minimal
In the literature various instruments are described to esti- trauma. Additional studies are needed to determine the
mate the 10-year fracture risk. One of the most popular is mechanisms underlying these fractures and the characteris-
the “Derived fracture Risk Assessment” or “DeFRA” which in- tics of patients at risk for them.
cludes a number of risk factors, such as family history of hip Treatment with bisphosphonates has been associated with
fracture, smoking, use of immunosuppressant drugs, hyper- higher risk of atrial fibrillation in some (36-38) but not all
thyroidism, alcohol abuse, previous vertebral or femoral frac- studies (39, 40). In 2011, the Food and Drug Administration
ture, rheumatoid arthritis or other autoimmune diseases (19). (FDA) has concluded that there were not enough reasons to
Individuals at high risk for fractures, as indicated by DeFRA suspect that treatment with bisphosphonates could induce
or other similar algorithms, are candidate for treatment re- atrial fibrillation. Moreover, a reduced risk of myocardial in-
gardless of BMD values. farction was recently observed during bisphosphonate treat-
ment in patient with rheumatoid arthritis (41).
Drugs Osteonecrosis of the jaw (ONJ) is a rare event in patients
Pharmacological agents against osteoporosis either de- treated with bisphosphonates and the level of evidence and
crease bone resorption to produce secondary gains in bone prediction of risk factors are relatively low (42). From a
mass or directly stimulate increases in bone mass (20). A pathological point of view, ONJ consists in a chronic os-
brief overview of the main drugs currently available to treat teomyelitis caused by germs of the oral flora, in particular
osteoporosis is provided in the following subsections. actinomyces (43). However, the pathogenesis of ONJ has
not yet been clearly defined. The main risk factors for ONJ
Bisphosphonates include prolonged treatment with oral bisphosphonates, cor-
Bisphosphonates are sintetic compounds with anti-resorptive ticosteroid therapy or immunosuppressive agents. Tooth ex-
activity (21). They act on bone through binding to hydroxyap- traction and dental and periodontal diseases are the main
atite and inhibiting osteoclast activation. Bisphosphonates predisposing factors (44, 45). Cases of ONJ have been de-
possess high affinity for bone and little effect on other organ scribed also in subjects who have never been treated with
systems. Pharmacokinetics of bisphosphonates explain their bisphosphonates (43).
overall good tolerability. Bisphosphonates have a poor in- Musculoskeletal pain, usually reversible after discontinuation
testinal absorption and therefore show low plasma levels af- (46, 47), ocular inflammation (48), urticaria (49), or mucositis
ter oral administration (21). Circulating levels of bisphospho- (50) have rarely been reported after use of bisphosphonates.
nates quickly decrease due to fast adhesion to bone surface,
so that the plasma half-life is very short, contrary to the half- Denosumab
life of bisphosphonate depots in the bone which is probably Denosumab is a human monoclonal antibody that blocks the
up to 10 years or longer (21). Bisphosphonates currently interaction of receptor activator of nuclear factor kB ligand
registered in Europe for the treatment of osteoporosis in- (RANKL) with receptor activator of nuclear factor kB (RANK),
clude alendronate, clodronate, etidronate, ibandronate, rise- whereby inhibiting bone resorption strongly and rapidly (51).
dronate, and zoledronate. Several formulations bisphospho- In postmenopausal women with low BMD, denosumab ad-
nates are available for the management of osteoporosis ministered subcutaneously 60 mg every 6 months increased
(e.g., oral and intravenous formulations, with weekly monthly BMD by 1 to 7% depending on the skeletal site (51). The in-
and annual dosing schedules). Dosing convenience is a key creases in BMD are higher than those obtained with the
element in the long-term management of a chronic disease. more potent bisphosphonates (51). In postmenopausal os-
Studies performed to assess adherence with once-monthly, teoporotic women, denosumab decreased the risk of verte-
once-weekly or once-daily dosing suggest that adherence bral and non-spine fractures by 70% and 20%, respectively
with either weekly or monthly dosing is significantly better (52). Denosumab slowed bone turnover also in older men re-
than with once-daily formulations (22). ceiving androgen-deprivation therapy for prostate cancer, in-
All approved bisphosphonates have shown to decrease bone creasing BMD by 4 to 7% as well as decreasing the inci-
turnover in a dose-dependent manner (21). While all bispho- dence of vertebral fractures by 60% and the incidence of
sphonates reduce vertebral fracture risk and increase BMD, multiple fractures by 70% (53).
only some of them are effective at reducing the risk for non- An association with ONJ has been observed in denosumab
vertebral and hip fractures (21). registration trials, although the event appears to be extreme-
Gastrointestinal side effect are quite common and can be ly rare (6 cases/4450 patients) (54). The pathogenesis of this
partially prevented by instructing the patient on how to take side effect has not yet been clearly defined, but it seems rea-
the drug (21). Also, weekly or monthly formulations decrease sonable to equate denosumab to bisphosphonates in this re-

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R. Bernabei et al.

gard. Cases of atypical femoral subtrochanteric/diaphyseal In osteoporotic women with prevalent vertebral fractures, rh-
fractures similar to those reported in patients treated with PTH decreases the incidence of new vertebral fractures by
bisphosphonates have been described in women with post- 65% and non-vertebral fractures by 53% (72). The best can-
menopausal osteoporosis treated with denosumab (55-57). didates for teriparatide and rhPTH(1-84) treatment are pa-
The length of exposure to denosumab at the time of atypical tients with pre-existing osteoporotic fractures, patients with
fracture diagnosis was longer than 2.5 years. Based on data very low BMD and those with unsatisfactory response to anti-
from the FREEDOM study, the incidence of atypical fractures resorptive therapy. The effects of the combination therapy
is extremely low (1 case/4450 patients) (54). However, no re- with rhPTH(1-84) and alendronate on BMD are controversial,
liable estimates can be given based on available data. with some authors reporting no synergy (73), while others
found an additive effect (74). However, according to guide-
Hormone replacement therapy (HRT) lines, the combined treatment with recombinant PTH and bis-
Treatment of osteoporotic women with HRT to prevent frac- phosphonates should not exceed 24 months (74). The safety
tures has been a long-standing controversial issue. Estrogen profile of teriparatide is overall good. A transient increase in
replacement, alone or in combination with tibolone (a syn- serum calcium levels and calcium renal excretion without
thetic steroid with estrogenic and androgenic properties), in- clinical manifestation has been reported. Absolute contraindi-
creases bone mass (58). The Women’s Health Initiative trial cations to teriparatide include primary hyperparathyroidism,
showed that the incidence of osteoporotic fractures was re- Paget’s disease of bone, previous radiation therapy of the
duced by 24%, with a 34% risk reduction for hip and verte- skeleton and primary or metastatic bone cancer (20).
bral fractures (58). However, long-term side effects, in partic-
ular the development of breast cancer, risks of cardiovascu- Strontium ranelate (SR)
lar events and thromboembolism, limit the use of HRT as a SR is adsorbed onto the bone surface and increases bone
countermeasure to osteoporosis. HRT is indeed no longer strength by being incorporated in a dose-dependent manner
recommended for the prevention and treatment of post- into bone tissue to change the crystal structure without af-
menopausal osteoporosis. fecting mineralization (75). SR increases bone formation
markers, reduces bone resorption markers and increases
Selective estrogen receptor modulators (SERMs) BMD progressively and dose-dependently (76, 77). In post-
SERMs are synthetic molecules that bind to the estrogen re- menopausal osteoporotic women during long term treatment
ceptor thereby acting as estrogen agonists on bone and liver (4 years), SR decreased the incidence of vertebral fractures
and as antagonists on breast and genitor-urinary tract. by 33% (78). SR also decreases the incidence of non-verte-
Raloxifene at the dose of 60 to 120 mg daily increases BMD bral fractures by about 15% and even more (31%) in the old-
by 2 to 3% at the lumbar spine and femoral neck (59, 60). est women (79, 80). The European Medicines Agency (EMA)
Based on data from the MORE study, raloxifene reduces the Committee for Medicinal Product for Human Use (CHMP)
incidence of vertebral fractures by 40 to 50%, with no effect recommended SR only be used for the treatment of severe
on non-vertebral fractures (61). Raloxifene also reduces the osteoporosis in men and postmenopausal women at high
risk of estrogen receptor-positive breast cancer, whilst the risk of fracture (81).
impact on cardiovascular risk is controversial (62-65). The most common side effects of SR therapy are nausea
Bazedoxifene at the dose of 20 to 40 mg daily decreases and diarrhea which usually develop at the beginning of the
bone turnover markers, while increasing BMD of the lumbar treatment and generally disappear after 3 months of therapy.
spine by 2% and preventing bone loss at the hip (66, 67). In Albeit rarely, SR administration has been associated with se-
postmenopausal osteoporotic women, bazedoxifene de- vere, potentially lethal, skin reactions, such as drug reaction
creases the risk of vertebral fractures by 40% of non-verte- with eosinophilia and systemic symptoms (DRESS),
bral fracture in high-risk patients (67). Stevens-Johnson syndrome and toxic epidermal necrolysis
Major concerns regarding side effects of SERMs are related to (82-85).
an increased risk of thrombotic and thromboembolic events. Recently, the EMA warned against a possible association
Overall, the size of this side effect is comparable to what is between the use of SR and cardiovascular events, above all
observed during HRT (68). The incidence of thrombotic events myocardial infarction (86). SR is therefore contraindicated in
is higher during the first 2 years of treatment, and progressive- patients with history of cardiovascular disease or uncon-
ly decreases thereafter (69). Hence, SERMs should not be trolled hypertension. In addition, it is recommended patients
prescribed or the treatment stopped in individuals at risk for be evaluated for cardiovascular risk before starting treatment
thromboembolism (i.e., bedridden patients). An increased risk with SR and at regular intervals during treatment. The possi-
for fatal stroke has also been reported in postmenopausal ble association between SR and venous thromboembolism
women over 5.6 years of follow-up (70). Less relevant side ef- (VTE) makes the drug contraindicated also in patients with
fects associated with SERMs include worsening of post- current VTE or a history of VTE, as well as in those who are
menopausal symptoms such as leg cramps or vasomotor in- temporarily or permanently immobilized (87). Taking all this
stability, especially at the beginning of treatment (71). into account, SR is not a first-choice option in older osteo-
porotic patients (88).
Recombinant human PTH
Recombinant 1-34 fragment of human PTH − rhPTH(1- Other “non-hormonal” drugs and novel therapeutic agents
34)teriparatide − and recombinant human intact PTH − rh- A number of drugs with beneficial effects on bone metabo-
PTH(1-84) − stimulate bone remodeling by inducing an in- lism and calcium-phosphorous homeostasis include calci-
crease in bone formation followed by a slower increase in tonin, ipriflavone, and thiazide diuretics. However, none of
bone resorption (72). They strongly increase BMD in the tra- these agents is currently recommended for osteoporosis
becular compartment, whereas their effect appears lower treatment because either ineffective or not supported by ad-
than bisphosphonates in the cortical sites. equate evidence.

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Screening, diagnosis and treatment of osteoporosis: a brief review

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treatment of vitamin D deficiency. Reumatismo. 2011;63:129-147.
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some clinical correlates urge health professionals to aban- menopausal osteoporosis and sarcopenia. J Osteoporos. 2011; 2011:536735.
17. Paterson DH, Warburton DER. Physical activity and functional limitations
don the old notion of osteoporosis as a mere “natural
in older adults: a systematic review related to Canada’s Physical Activity
byproduct” of aging. Rather, the medical community is called
Guidelines. Int J Behav Nutr Phys Act. 2010;7:38.
to promote an adequate awareness on the subject and put in 18. Kanis JA, McCloskey EV, Johansson H, et al. European guidance for the
place large-scale screening and diagnostic procedures in or- diagnosis and management of osteoporosis in postmenopausal women. Os-
der to identify people with osteoporosis or at risk of develop- teoporos Int. 2013;24:23-57.
ing the condition. This would allow the early correction of risk 19. Adami S, Bianchi G, Brandi ML, et al. Validation and further development
factors for osteoporosis and the prompt institution of anti-os- of the WHO 10-year fracture risk assessment tool in Italian postmenopausal
teoporotic treatments. In this regard, it needs to be consid- women: project rationale and description. Clin Exp Rheumatol. 2010;28:561-
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solely on BMD, but on comprehensive fracture risk assess- 20. Varenna M, Bertoldo F, Di Monaco M, et al. Safety profile of drugs used in
the treatment of osteoporosis: a systematical review of the literature. Reuma-
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tismo. 2013;4:143-166.
available. Each drug (or class of drugs) possesses specific
21. Fleisch H. Bisphosphonates in osteoporosis. Eur Spine J. 2003;12:142-146.
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scribed or avoided in selected patient populations. New and oral bisphosphonates and the impact on adherence. Am J Med.
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what has rightly been called the osteoporosis epidemic. of once weekly alendronate 70 mg with concomitant non-steroidal anti-in-
flammatory drug use. Aliment Pharmacol Ther. 2005;21:599-607.
Acknowledgements 24. Greenspan S, Field-Munves E, Tonino R, et al. Tolerability of once-week-
This work was partly supported by the “Centro Study Achille ly alendronate in patients with osteoporosis: a randomized, double- blind,
placebo-controlled study. Mayo Clin Proc. 2002;77:1044-52.
e Linda Lorenzon”. The Authors apologize to those re-
25. Eisman JA, Rizzoli R, Roman-Ivorra J, et al. Upper gastrointestinal and over-
searchers whose excellent work could not be cited due to the
all tolerability of alendronate once weekly in patients with osteoporosis: re-
vast literature on the subject and space limitations. sults of a randomized, double-blind, placebo controlled study. Curr Med Res
Opin. 2004;20:699-705.
26. Bobba RS, Beattie K, Parkinson B, et al. Tolerability of different dosing reg-
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