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    "titulosAlternativos" => array:1 [
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        "titulo" => "Actualizaci&#243;n 2011 del consenso Sociedad Espa&#241;ola de Reumatolog&#237;a de osteoporosis"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Updating knowledge on the different aspects of osteoporosis &#40;OP&#41; is still needed because of its high prevalence&#44; its complications&#44; and the associated health and social spending&#46; At a time when the rational use of resources is important&#44; this document is&#44; in reality&#44; a corporate reflection in which we analyze new evidence on diagnosis&#44; risk factors for fracture&#44; follow up and treatment of OP&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">These recommendations are intended as a reference for therapeutic decision making to rheumatologists and all professionals who&#44; from the different levels of care&#44; are implicated in the treatment of OP&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Methodology</span><p id="par0015" class="elsevierStylePara elsevierViewall">Tasks were distributed for the elaboration of this document and commentary to each part&#46; The structure of the document is based on questions relevant to clinical practice in OP&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Each panelist was first assigned one or several parts of the consensus for write up&#46; Once completed&#44; the whole panel was distributed for comment&#46; After that&#44; members of the research unit &#40;RU&#41; of the Spanish Society of Rheumatology &#40;SER&#41; unified&#44; categorized&#44; classified and summarized all of the comments for their evaluation prior to the panel getting together&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">A meeting of the nominal group was carried out&#44; moderated by members of the RU of SER&#46; In this meeting&#44; modification proposals in relation to format and content&#44; including the recommendations&#44; were performed&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Then&#44; a Delphi survey was performed and consensus recommendations were voted on &#40;anonymously online&#41;&#46; The aggregated results were shown to all the panelists &#40;modified Delphi&#41;&#46; Recommendations with a degree of agreement &#40;DA&#41; of less than 70&#37; were reedited and voted for a second time&#46; Agreement is defined if&#44; on a scale of 1 &#40;complete disagreement&#41; to 10 &#40;complete agreement&#41;&#44; the vote is 7 or more&#46; The level of evidence &#40;LE&#41; and degree of recommendation &#40;DR&#41; are classified according to the model proposed by the Center for Evidence Based Medicine of Oxford<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> by members of the RU of SER&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">With all of this information the definite document was written up&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Diagnosis and Evaluation</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What Is Osteoporosis&#63;</span><p id="par0040" class="elsevierStylePara elsevierViewall">OP has been defined in the consensus conference of the National Institute of Health as a skeletal disease characterized by reduced bone resistance that predisposes an increase in the risk of fracture &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Bone resistance reflects the integration of bone density and bone quality&#46; At the same time&#44; bone density is determined by the peak value of bone mass and the magnitude of its loss&#44; while bone quality depends on architecture&#44; bone exchange&#44; the accumulation of microlesions and mineralization&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">When Should I Suspect a Case of Osteoporosis&#63;</span><p id="par0050" class="elsevierStylePara elsevierViewall">There is no current population survey protocol that is universally accepted for the identification of persons with OP&#46; Patients are identified by a strategy of case by case search based on a history of one or more fragility associated fractures or the presence of significant clinical risk factors&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In certain groups of patients&#44; mainly the elderly and postmenopausal women&#44; we must maintain a high degree of suspicion and actively search for risk factors &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What Is Considered an Osteoporotic Fracture&#63;</span><p id="par0060" class="elsevierStylePara elsevierViewall">An osteoporotic fracture or fragility fracture is conditioned by low impact trauma&#46; A fall from a standing or sitting position is included in this concept&#46; Fractures that occur as a consequence of sports or accidents are excluded &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">It is estimated that close to 40&#37; of Caucasian women will have at least one fracture after the age of 50&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;9</span></a> The most frequent and relevant are those of the proximal femur&#44; the spinal column and the distal forearm&#46; On the other hand&#44; we must point out that fractures of the cranium or face are excluded from this definition&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What Is High Risk of Osteoporotic Fracture&#63;</span><p id="par0070" class="elsevierStylePara elsevierViewall">As occurs with OP&#44; there is no universally accepted survey to identify the population with a high risk of fracture&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The risk of osteoporotic fracture is determined by the presence of one or more risk factors including low bone mineral density &#40;BMD&#41;&#46; The combination of risk conferred by a low BMD with clinical risk factors<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> allows for a better estimate of risk&#46; We consider a high risk for fracture when there are at least 2 high risk factors &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Having a tool for the calculation of osteoporotic fracture risk would permit the identification of persons with a high risk who would merit early intervention and reduce the number of unnecessary treatments administered to low risk patients&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Different instruments that estimate the risk of fracture based on risk factors have been developed &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Of them&#44; the most important is the FRAX tool<span class="elsevierStyleSup">&#169;</span>&#44; a software tool sponsored by the WHO&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> which can be applied with and without BMD&#46; The FRAX<span class="elsevierStyleSup">&#174;</span> algorithms calculate the absolute 10 year probability of fracture into a group of &#8220;major fractures&#8221; &#40;clinical vertebral&#44; forearm&#44; hip and humeral fractures&#41; and isolated hip fractures&#46; It is currently the most recommended instrument used to calculate the risk of osteoporotic fracture&#46; However&#44; as everything&#44; it has limitations and the medical judgment of the clinician is still fundamental&#46; The risk of a major fracture calculated by FRAX<span class="elsevierStyleSup">&#169;</span> in the Spanish population over 15&#37; is very specific for osteoporosis&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">There is no consensus in the medical literature on the threshold above which the risk for a fracture would be considered &#8220;high&#8221; in the Spanish population&#46; An approximation would be&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8211;</span><p id="par0090" class="elsevierStylePara elsevierViewall">Absolute 10 year risk of fracture &#60;10&#37;&#58; low&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8211;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Absolute 10 year risk of fracture &#8805;10&#37; and &#60;20&#37;&#58; moderate&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8211;</span><p id="par0100" class="elsevierStylePara elsevierViewall">Absolute 10 year risk of fracture &#8805;20&#37;&#58; low&#46;</p></li></ul></p><p id="par0105" class="elsevierStylePara elsevierViewall">If FRAX<span class="elsevierStyleSup">&#169;</span> is employed&#44; its systemic application is recommended in patients in whom&#58; &#40;a&#41; the indication of a BMD is being evaluated&#59; &#40;b&#41; the onset of treatment is being evaluated for OP&#44; and &#40;c&#41; they are over 65 years of age&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What History and Examination Data Are Important&#63;</span><p id="par0110" class="elsevierStylePara elsevierViewall">If OP is suspected&#44; with the aim of evaluating the risk of fracture and the cause of OP&#44; we recommend obtaining the following data&#58; age&#44; ethnicity&#44; history of toxic habits &#40;tobacco&#44; alcohol&#41;&#44; dietary intake of calcium and vitamin D&#44; degree of exposure to sunlight&#44; menstrual history &#40;age at menopause and menarche&#41;&#44; obstetric history &#40;interventions&#44; surgical menopause&#44; hypogonadism&#41;&#44; osteopenia associated diseases and drugs&#44; previous trauma&#44; family or personal history of fragility fractures and conditions associated to falls&#44; as well as data regarding recent or prior fractures &#40;LE 5&#59; DR D&#59; DA 95&#37;&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The presence of present or prior fractures should be evaluated determining episodes of acute and&#47;or chronic back pain&#44; progressive reduction in height&#44; etc&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> It is important to remember that OP is asymptomatic and that more than half of the vertebral fractures are also asymptomatic&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">It is recommended that physical examination record weight&#44; height&#44; the existence of skeletal deformities and palpation&#47;percussion of the spine be carried out &#40;LE 5&#59; DR D&#59; DA 90&#37;&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The relationship between the body mass index and BMD is well known&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The possible existence of skeletal deformities should be established by the presence of dorsal kyphosis&#44; a reduction of the space between the ribs and the pelvis&#44; etc&#46;&#44; and palpation&#47;percussion should be directed to the localization of painful zones of the locomotor system&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> General physical examination may provide data on other diseases associated to a reduction in bone mass&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What Laboratory Data Is Important&#63;</span><p id="par0130" class="elsevierStylePara elsevierViewall">Laboratory tests are performed to identify associated processes and perform a differential diagnosis with other diseases associated to bone fragility&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;21</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">When OP is suspected&#44; one should request&#58; complete blood count&#44; alkaline phosphatase&#44; creatinine&#44; serum proteins&#44; erythrocyte sedimentation rate&#44; serum calcium and phosphorus and 24<span class="elsevierStyleHsp" style=""></span>h urinary calcium excretion &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">It is advisable to determine during the initial visit what the levels of 25-hydroxyvitamin D &#40;25-&#91;OH&#93;-D<span class="elsevierStyleInf">3</span>&#41;&#44; parathyroid hormone &#40;PTH&#41; and thyroid stimulating hormone are &#40;LE 5&#59; DR D&#59; DA 80&#37;&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In case an associated disease is suspected&#44; pertinent laboratory tests should be performed &#40;LE 5&#59; DR D&#59; DA 95&#37;&#41;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The systematic determination of bone markers is not recommended for the diagnosis and evaluation of patients with OP&#46; Their measurement is useful to identify subjects with a greater risk of fracture and especially to evaluate in an early manner response to&#44; both antiresorptive as well as bone forming treatments &#40;LE 2c&#59; DR C&#59; DA 80&#37;&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Bone remodeling markers provide additional and complementary information to the study of BMD&#46; Osteocalcin&#44; bone alkaline phosphatase and type I procollagen aminoterminal propeptide stand out as bone formation markers and pyridinolynes&#44; carboxy and aminoterminal telopeptides of type I collagen &#40;serum CTX and urine NTX&#41; and tartrate 5b resistant acid phosphatase stand out among those associated to resorption&#46; These are more sensitive and specific than classic markers such as total alkaline phosphatase and hydroxyproline&#46; It is important to take into account biological variability and circadian rhythm in their correct interpretation and therefore establish an adequate schedule to obtain samples&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;24</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">When Is it Advisable to Request Spinal X-rays&#63;</span><p id="par0160" class="elsevierStylePara elsevierViewall">Spine radiographs are not useful to assess the decrease in BMD&#44; but allow the diagnosis of fractures&#44; including asymptomatic ones&#46; We must remember that the presence of prior vertebral fracture is a significant risk factor for new fractures&#44; both vertebral and non-vertebral&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#8211;29</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">In patients with suspected or diagnosed OP&#44; it is recommended to perform an initial spinal X-ray for detecting fractures &#40;LE 2b&#59; DR B&#59; DA 95&#37;&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">If there is suspicion of vertebral fracture during follow up&#44; a spinal X-ray is recommended &#40;LE 2b&#59; DR B&#59; DA 100&#37;&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">The panel believes that for the diagnosis of spinal fractures&#44; lateral&#44; dorsal and lumbar spine X-rays&#44; with focus on D8 and L2&#44; respectively<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> are sufficient &#40;LE 2a&#59; DR C&#59; DA 100&#37;&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Anteroposterior projections are not essential for diagnosis but can provide additional information&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">When Is it Indicated to Perform a Bone Densitometry&#63;</span><p id="par0185" class="elsevierStylePara elsevierViewall">A densitometric survey of the general population is not cost-effective<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> and there is great variability regarding indications for densitometry&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;32&#8211;37</span></a> Until today there are no validated tools that satisfactorily quantify the risk of fracture or a consensus on the definition of risk of fracture that helps determine a therapeutic intervention&#46; The evaluation of BMD along with other risk factorsis useful for the diagnosis and follow up of patients&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The indication for performing a densitometry should be based on clinical criteria that allow the selection of patients in which the use of this technology is efficient &#40;LE 2b&#59; DR B&#59; DA 95&#37;&#41;&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Before requesting for it is essential to be certain that the result will help determine the therapeutic decision to be taken&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">A baseline densitometry is recommended in the following &#40;LE 5&#59; DR D&#59; DA 75&#37;&#41;&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">1&#46;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Women with early menopause and any major risk factors for fracture&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">2&#46;</span><p id="par0210" class="elsevierStylePara elsevierViewall">Postmenopausal women of any age and men over 50 with at least one major risk factor for fracture&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">3&#46;</span><p id="par0215" class="elsevierStylePara elsevierViewall">A history of fragility fracture in patients over 50&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">4&#46;</span><p id="par0220" class="elsevierStylePara elsevierViewall">Underlying disease or chronic treatment with medication associated to bone loss&#44; especially glucocorticoids&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">5&#46;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Women over 65 years of age and men &#62;70 without known risk factors at least in one occasion if patient request it&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">6&#46;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Evaluation of pharmacologic treatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">7&#46;</span><p id="par0235" class="elsevierStylePara elsevierViewall">If the FRAX<span class="elsevierStyleSup">&#169;</span> is employed&#44; a densitometry is recommended in women 65 and older and those younger but with a major risk factor for fracture according to the FRAX<span class="elsevierStyleSup">&#169;</span>&#44; equivalent to a 65 year old woman with no risk factors de riesgo &#40;Spanish FRAX 3&#46;6&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;40</span></a></p></li></ul></p><p id="par0240" class="elsevierStylePara elsevierViewall">To detect significant changes with a confidence interval &#40;CI&#41; of 95&#37;&#44; these should be&#44; at least&#44; 2&#46;8 times the variation coefficient &#40;minimum significant change&#41;&#46; In clinical practice its application is difficult because very strict precision measures are needed&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> The use of another concept is more practical&#44; &#8220;the smallest detectable difference&#8221; which is established in 2&#37; &#40;change in lumbar BMD<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;05<span class="elsevierStyleHsp" style=""></span>g&#47;cm<span class="elsevierStyleSup">2</span>&#44; total femur<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;04<span class="elsevierStyleHsp" style=""></span>g&#47;cm<span class="elsevierStyleSup">2</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Although major changes in BMD are detected on the lumbar spine&#44; it is also useful to monitor the hip because it is less dependent on artifacts produced by degenerative change&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Which Densitometric Technique Is the Most Adequate&#63;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Dual energy X-ray absorciometry &#40;DXA&#41; is recommended as the reference technique for measuring BMD &#40;LE 2b&#59; DR B&#59; DA 100&#37;&#41;&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">DXA is a technique that has good precision&#44; low radiological exposure and allows for measurement of BMD both in the axial as well as in the peripheral skeleton&#46; It is considered the best technique to evaluate BMD&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;41&#44;42</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What Is Dual Energy X-ray Absorciometry Good for&#63;</span><p id="par0255" class="elsevierStylePara elsevierViewall">Results of BMD obtained through DXA predict the future risk of fracture due to OP&#44; both in postmenopausal women as in elderly males&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#8211;49</span></a> But in addition&#44; according to WHO&#44; to diagnose OP it is necessary to know the value of the BMD in the femur and lumbar spine through a central DXA&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a> Currently&#44; central DXA is the only validated technique to follow up and for evaluation of therapeutic response&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">To perform a diagnosis of OP&#44; we recommend carrying out a DXA&#44; as long as it is possible on the hip and lumbar spine &#40;LE 2b&#59; DR B&#59; DA 95&#37;&#41;&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">A lateral projection of the spine should not be used for the diagnosis of OP&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">If DXA of the lumbar spine or hip is impossible&#44; it is recommended that DXA be performed on the distal third of the radius of the non-dominating forearm &#40;LE 2b&#59; DR B&#59; DA 90&#37;&#41;&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">This may occur in case of anatomical alterations &#40;scoliosis&#44; degenerative problems&#44; multiple vertebral fractures&#44; morbid obesity&#41; or technical problems &#40;presence of metallic elements after spinal surgery&#44; hip arthroplasty&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">When necessary&#44; control DXA of the hip and the spine should be performed with the same equipment &#40;LE 1b&#59; DR A&#59; DA 90&#37;&#41;&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">Long-term precision or reproducibility of DXA&#59; expressed as a variation coefficient&#44; varies according to the measurement area and the equipment used from 1 to 2&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">53&#8211;55</span></a> In women undergoing treatment for postmenopausal OP&#44; densitometric controls should be performed every 2&#8211;3 years&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> In general&#44; codensitometric controls are not recommended before 2 years because it has been seen that some patients who lose bone mass during the first year may regain it during the second&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">Ultrasound&#44; peripheral DXA equipment and central or peripheral quantitative computerized tomography are useful to predict an elevated risk of fracture but should not be used for diagnosis&#44; follow up or evaluation of therapeutic response in patients with OP &#40;LE 1a&#59; DR A&#59; DA 95&#37;&#41;&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">There are other techniques to measure BMD in the peripheral skeleton&#44; such as phalangeal&#44; knee and calcaneus DXA&#44; and calcaneus ultrasound&#46; They are cheaper&#44; easier to handle and faster in comparison to central DXA but&#44; among other limitations&#44; their precision is low&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;52&#44;56&#44;57</span></a> They are useful to predict the future risk of fracture and may have some value when it is impossible to perform a central DXA&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;52&#44;56</span></a> Peripheral quantitative computed tomography is a rapidly developing imaging technique&#46; It allows for volumetric BMD measurement of the lumbar spine&#44; hip and distal radiums&#44; but its results are not comparable to those obtained through DXA&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">How Is Osteoporosis Diagnosed&#63;</span><p id="par0300" class="elsevierStylePara elsevierViewall">Diagnosis of OP is based on the densitometric criteria established by WHO for white postmenopausal women &#40;BMD values under &#8722;2&#46;5 standard deviations &#40;SD&#41; &#40;<span class="elsevierStyleItalic">T</span>-score inferior to &#8722;2&#46;5&#41; and&#47;or the presence of fragility fractures &#40;LE 2c&#59; DR B&#59; DA 90&#37;&#41;&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Cutpoints for BMD measured by DXA on the lumbar spine and hip<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">59&#8211;61</span></a> correspond to normal&#44; values of BMD<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>&#8722;1 SD in relation with the mean of young adults &#40;<span class="elsevierStyleItalic">T</span>-score<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>&#8722;1&#41;&#59; osteopenia or low bone mass&#44; BMD values between &#8722;1 and &#8722;2&#46;5 SD &#40;<span class="elsevierStyleItalic">T</span>-score between &#8722;1 and &#8722;2&#46;5&#41;&#59; OP&#44; BMD values of &#60;&#8722;2&#46;5 DE &#40;<span class="elsevierStyleItalic">T</span>-score<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#8722;2&#46;5&#41;&#44; and established OP when the previous condition is associated to &#8805;1 osteoporotic fracture&#46; The same cutpoints have been proposed for adult males&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Treatment</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What Non-pharmacologic Methods Should we Use&#63;</span><p id="par0310" class="elsevierStylePara elsevierViewall">The following general measures should be recommended to all of the population&#44; with special emphasis on osteoporotic patients&#58; physical exercise&#44; elimination of toxic habits&#44; balanced diet&#44; adequate intake of calcium and vitamin D&#44; preventing falls &#40;LE 1a&#59; DR A&#59; DA 100&#37;&#41;&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">Moderate to intense physical exercise increases bone mass in young patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">62&#8211;66</span></a> as well as in adults&#44; although less intensely&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> There is no consistent evidence on the effect over bone mass in elderly patients&#44; but performing it reduces the risk of fractures&#44; probably by reducing falls&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">68&#8211;70</span></a></p><p id="par0320" class="elsevierStylePara elsevierViewall">Avoidance of sedentarism and the performance of moderate physical activity are recommended&#44; taking into account the patients&#8217; age&#44; physical status and other diseases &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">A balanced diet with an adequate consumption of proteins&#44; avoidance of excess salt and moderate sun exposure are also recommended &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">A daily calcium intake of 1000<span class="elsevierStyleHsp" style=""></span>mg and serum 25-OH vitamin D levels of &#8805;30<span class="elsevierStyleHsp" style=""></span>ng&#47;ml &#40;75<span class="elsevierStyleHsp" style=""></span>mmol&#47;l&#41; is recommended &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">Sometimes&#44; common diets do not provide these calcium requirements and therefore must be modified or supplemented with pharmacological calcium which&#44; if taken isolatedly&#44; has not shown a significant effect on the reduction of fractures in postmenopausal OP&#44; but help reduce the loss of bone mass&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">71&#8211;73</span></a> In healthy women it has been suggested to increase cardiovascular risk<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74&#44;75</span></a> and renal litiasis&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> but this is a controversial and unclear subject&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall">Approximately 50&#37; of the osteoporotic population presents low serum concentrations of vitamin D and it is advisable to supplement it with 800&#8211;1000<span class="elsevierStyleHsp" style=""></span>U in all patients&#46; The efficacy of vitamin D supplements in the prevention of fractures is controversial&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">77&#8211;82</span></a> There is evidence that it reduces fractures in institutionalized elderly patients when administered with calcium&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">77&#8211;82</span></a> Additionally&#44; some studies indicate that vitamin D supplements may reduce falls<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> but other do not&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall">In patients receiving anticatabolic treatment&#44; we recommend an intake of 1000<span class="elsevierStyleHsp" style=""></span>mg of calcium and 800&#8211;1000<span class="elsevierStyleHsp" style=""></span>U of vitamin D is recommended &#40;LE 1a&#59; DR A&#59; DA 95&#37;&#41;&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">In the elderly&#44; measures directed at reducing the risk of falls&#44; promoting the use of canes&#44; avoiding psychopharmacologic agents&#44; correcting visual disturbances and adapting living spaces are recommended&#46; In high risk populations&#44; hip protectors may be employed&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">83&#8211;85</span></a></p><p id="par0355" class="elsevierStylePara elsevierViewall">For more information consult <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">How to Treat an Acute Vertebral Fracture&#63;</span><p id="par0360" class="elsevierStylePara elsevierViewall">The goals of treatment of a vertebral fracture are acute pain control and functional recovery &#40;LE 2b&#59; DR B&#59; DA 100&#37;&#41;&#46;</p><p id="par0365" class="elsevierStylePara elsevierViewall">It is very important to inform patients that fractures may take up to 3 months to consolidate and that pain will gradually decrease and improve function&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a></p><p id="par0370" class="elsevierStylePara elsevierViewall">Oral analgesics&#44; relative rest&#44; orthoses and rehabilitation are the mainstays of treatment &#40;LE 2b&#59; DR B&#59; DA 90&#37;&#41;&#46;</p><p id="par0375" class="elsevierStylePara elsevierViewall">Oral analgesics are first-line drugs to reduce the pain of vertebral fractures&#46; The choice should be appropriate to the magnitude of pain&#46; In cases where the pain reaches a significant intensity and conventional painkillers failed&#44; we recommend using opioids&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">87&#44;88</span></a></p><p id="par0380" class="elsevierStylePara elsevierViewall">If complete rest is indicated&#44; return to sitting and walking should be accomplished in the shortest possible time&#46; During the acute episode there may be a need for prescription orthotics and&#44; once control of acute pain is achieved&#44; rehabilitation may be useful &#40;LE 5&#59; DR B&#59; DA 95&#37;&#41;&#46;</p><p id="par0385" class="elsevierStylePara elsevierViewall">A back brace should be used with caution as excessive spinal immobility could increase OP&#44;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a> and rehabilitation should be directed by a specialist&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a></p><p id="par0390" class="elsevierStylePara elsevierViewall">In patients with acute vertebral fractures with pain that does not respond to the above measures&#44; vertebroplasty or kyphoplasty may be indicated &#40;LE 1c&#59; DR B&#59; DA 95&#37;&#41;&#46;</p><p id="par0395" class="elsevierStylePara elsevierViewall">Several observational studies have shown rapid analgesic effect and reduced period of immobilization in a high percentage of patients&#44; in the short to medium term&#44; but this does not exempt these procedures from secondary&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">91&#8211;96</span></a> Recently&#44; two controlled clinical trials have not shown that vertebroplasty was more effective than other conservative options&#46;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">97&#44;98</span></a> Another controlled trial has found benefit with the use of vertebroplasty in a subgroup of patients with persistent intense symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> Based on the above&#44; patients who are going to undergo these interventions should be carefully selected&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a></p><p id="par0400" class="elsevierStylePara elsevierViewall">Currently&#44; no generalization can be recommended for vertebroplasty or kyphoplasty to treat osteoporotic vertebral fractures &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What Drugs Should Be Recommended in Osteoporosis&#63;</span><p id="par0405" class="elsevierStylePara elsevierViewall">The objective of pharmacologic treatment of OP is to reduce the risk of fracture &#40;LE 1a&#59; DR A&#59; DA 100&#37;&#41;&#46;</p><p id="par0410" class="elsevierStylePara elsevierViewall">Pharmacological intervention is performed with therapeutic agents capable of acting in both phases of bone remodeling&#46; At present&#44; there are three categories of anti-osteoporotic drugs&#44; antiresorptive and anti-catabolic&#44; which inhibit bone resorption by acting on osteoclasts and their precursors&#44; decrease the rate of activation of bone remodeling&#44; increase bone mineral density and preserve the microarchitecture of the bone&#59; and anabolic drugs&#44; which act on osteoblasts or their precursors resulting in increased bone remodeling&#44; with bone formation increased to a greater extent than resorption&#44; which in time increases mass and bone strength&#44; as well as agents with a double mechanism of action where there is a combination of both&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">101&#44;102</span></a></p><p id="par0415" class="elsevierStylePara elsevierViewall">For more information regarding their indications&#44; efficacy in relation to the prevention of fractures and adverse events&#44; see <a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a>&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Antiresorptive Drugs or Anti-catabolic</span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Hormone Replacement Therapy</span><p id="par0420" class="elsevierStylePara elsevierViewall">Currently&#44; HRT should not be recommended for the treatment of postmenopausal OP&#44; except for women with early menopause&#44; intense climacteric symptoms or in the case of not being able to administer other OP drugs due to adverse effects or ineffectiveness &#40;LE 1c&#59; DR B&#59; DA 95&#37;&#41;&#46;</p><p id="par0425" class="elsevierStylePara elsevierViewall">Estrogens may reduce the incidence of vertebral and peripheral fractures&#44; although drugs such as alendronate are superior&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">103&#44;104</span></a> There is evidence that hormone replacement therapy &#40;HRT&#41; increases the risk of breast cancer&#44; heart disease&#44; stroke and venous thromboembolism&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Calcitonin</span><p id="par0430" class="elsevierStylePara elsevierViewall">Calcitonin can be administered as a preventive measure and as a second line treatment of postmenopausal OP&#44; after bisphosphonates&#44; and may be indicated in the treatment of recent symptomatic vertebral fractures &#40;LE 1c&#59; DR B&#59; DA 70&#37;&#41;&#46;</p><p id="par0435" class="elsevierStylePara elsevierViewall">Calcitonin prevents loss of BMD in the spine&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a> reduces the risk of new vertebral fractures in postmenopausal women with a history of vertebral fractures&#44; but not the risk of peripheral fractures&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">107</span></a> It also has an analgesic effect in patients with vertebral fractures&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">108</span></a> Its effectiveness seems to be maintained in the long term&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Raloxifene</span><p id="par0440" class="elsevierStylePara elsevierViewall">Raloxifene is recommended as second line treatment of postmenopausal OP &#40;LE 1a&#59; DR A&#59; DA 90&#37;&#41;&#46;</p><p id="par0445" class="elsevierStylePara elsevierViewall">Raloxifene decreases the loss of BMD<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">109</span></a> and reduces vertebral fracture risk in women with postmenopausal OP with and without fractures&#44; but does not reduce the risk of non-vertebral fractures&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">110&#44;111</span></a> In addition&#44; it decreases serum cholesterol and low-density lipoprotein cholesterol&#44; although it does not seem to reduce the risk of heart disease&#46; It also decreases the incidence of estrogen receptor positive breast cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">112</span></a> but is associated with increased thromboembolic events&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">113&#44;114</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Bazedoxifene</span><p id="par0450" class="elsevierStylePara elsevierViewall">Bazedoxifene is an alternative to raloxifene in the treatment of postmenopausal OP &#40;LE 1c&#59; DR B&#59; DA 83&#37;&#41;&#46;</p><p id="par0455" class="elsevierStylePara elsevierViewall">Bazedoxifene has demonstrated its protective action in BMD loss and reducing vertebral fractures in postmenopausal women with OP and&#44; like raloxifene&#44; has shown efficacy in reducing vertebral fractures&#44; except in high-risk fracture population &#40;post hoc&#41;&#46; At a dose of 20<span class="elsevierStyleHsp" style=""></span>mg the most common side effects&#44; cramps and hot flashes&#44; were matched to raloxifene and deep vein thrombosis was observed in 0&#46;4 and 0&#46;2&#37; of patients receiving bazedoxifene and placebo&#44;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">115&#44;116</span></a> respectively&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Bisphosphonates</span><p id="par0460" class="elsevierStylePara elsevierViewall">The panel recommends bisphosphonates &#40;BF&#41; as first-line drugs in the treatment of OP &#40;LE 1a&#59; DR A&#59; DA 100&#37;&#41;&#46;</p><p id="par0465" class="elsevierStylePara elsevierViewall">BF are currently the most widely used drugs in the treatment of OP&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">117</span></a> Its anti-fracture effectiveness has been amply demonstrated<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">118&#8211;121</span></a> and are generally well tolerated&#46; On the other hand&#44; the rate of adherence to treatment in the medium or long term &#40;1 year&#41; is low&#44; between 47&#37; in the monthly presentation and 30&#37; in the weekly presentation&#46; Therefore&#44; measures aimed at improving patient compliance must be implemented&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">122</span></a></p><p id="par0470" class="elsevierStylePara elsevierViewall">We do not have enough evidence to recommend one drug over another&#44; so the choice will be based on other factors such as dosage&#44; characteristics&#44; patient preferences and physician experience with the use of BF&#46;</p><p id="par0475" class="elsevierStylePara elsevierViewall">There is no general agreement on the optimal duration of treatment&#44; although an average period of 5 years is advised&#44; after which its continuation&#44; suspension or discontinuation or replacement by another drug should be evaluated&#44; taking into account the estimated residual risk of fracture at the time&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">123</span></a></p><p id="par0480" class="elsevierStylePara elsevierViewall">Before starting treatment&#44; an adequate calcium and vitamin D supplementation should be ensured as well as basic guidelines to follow&#58; BF should be taken in the morning &#40;standing or seated with a glass of 200<span class="elsevierStyleHsp" style=""></span>ml of water&#41;&#44; fasting since the previous day and waiting at least half an hour &#40;1<span class="elsevierStyleHsp" style=""></span>h for monthly dose&#41; before eating solid foods or drinking &#40;except water&#41;&#46;</p><p id="par0485" class="elsevierStylePara elsevierViewall">The different BF approved for use in OP will now be discussed&#46; For more information&#44; see <a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a>&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Etidronate</span><p id="par0490" class="elsevierStylePara elsevierViewall">Etidronate increases bone mass and moderately reduces the risk of vertebral fractures in women with OP&#44; with a duration of 4 years&#44;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">124&#44;125</span></a> but does not significantly reduce the risk of hip and non-vertebral fractures&#46; Its continued use can cause osteomalacia&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">126</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Alendronate</span><p id="par0495" class="elsevierStylePara elsevierViewall">Alendronate significantly reduces the risk of vertebral and non-vertebral fractures&#44; including the hip&#46; Currently&#44; the most common form of administration is a once weekly dosing of 70<span class="elsevierStyleHsp" style=""></span>mg&#46; Although optimal duration of treatment<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a> was observed when the drug was discontinued after 5 years of treatment&#44; 5 years later a decrease in lumbar and hip BMD was seen&#44; 3&#46;7 and 2&#46;4&#37; compared with when it was continued for 10 years and remodeling markers increased&#44; with no differences in fracture incidence between groups &#40;except clinical vertebral fractures&#41;&#44; so treatment may be maintained for 10 years&#44;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">128</span></a> but this also opens the possibility of a &#8220;therapeutic holiday&#8221; at 5 years due to the residual effect of the drug on the risk of fracture&#46;</p><p id="par0500" class="elsevierStylePara elsevierViewall">There is a presentation containing alendronate and vitamin D&#44; and generic alendronate sodium with a similar bioequivalence with the brand product&#46; Slight differences were observed in the in vitro decay<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">129</span></a> and esophageal transit&#44;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">130</span></a> raising doubts about some generic formulations&#44; which may have lower bioavailability and potency&#44; and greater ability to cause esophageal adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">131</span></a> Because generic prescribing is a central objective of health systems&#44; independent studies are needed for the clinician to prescribe generics without reserve&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">132</span></a></p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Risedronate</span><p id="par0505" class="elsevierStylePara elsevierViewall">Risedronate is effective in reducing the risk of vertebral and non-vertebral fractures&#44; including hip and postmenopausal OP in women with and without previous fractures&#46;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">133&#8211;137</span></a> The most commonly used dosage is 35<span class="elsevierStyleHsp" style=""></span>mg&#47;week orally<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">138</span></a> and there is also a presentation that allows its administration in doses of 75<span class="elsevierStyleHsp" style=""></span>mg monthly given in 2 consecutive days&#46; There is also a generic preparation&#46;</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ibandronate</span><p id="par0510" class="elsevierStylePara elsevierViewall">Ibandronate is effective in preventing vertebral fractures at a dose of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day orally in postmenopausal women with OP with and without prior fractures&#46; Efficacy in non-vertebral fractures is significant only in the subgroup with higher risk&#46; It has no efficacy in hip fracture&#46; The bioequivalent single dose of 150<span class="elsevierStyleHsp" style=""></span>mg may be used monthly&#46;<a class="elsevierStyleCrossRefs" href="#bib0600"><span class="elsevierStyleSup">120&#44;139&#8211;144</span></a> It may also be administered as an intravenous injection of 3<span class="elsevierStyleHsp" style=""></span>mg every 3 or 4 months&#44;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">145</span></a> which has an acceptable safety profile and may be performed as an outpatient procedure&#44;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">146</span></a> as an option for patients with obvious risk of compliance failure&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">147</span></a></p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Zoledronate</span><p id="par0515" class="elsevierStylePara elsevierViewall">This BF is marketed for intravenous use only&#46; Its standard dose is annually&#44; 5<span class="elsevierStyleHsp" style=""></span>mg&#44; day&#46; It is effective in reducing the incidence of clinical vertebral fractures&#44; morphometric&#44; non-vertebral and hip fractures over 3 years&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">148</span></a> It also reduces overall mortality in patients with hip fractures&#44;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">149</span></a> without a clear explanation in this respect&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">150</span></a> It is an alternative for patients with OP and increased risk of fractures or those who do not tolerate or are contraindicated oral BF&#46;</p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Adverse Events of Bisphosphonates</span><p id="par0520" class="elsevierStylePara elsevierViewall">The overall safety profile of BF is acceptable &#40;see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; However&#44; a number of adverse events potentially related to BF have been reported&#44; which may be serious&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">151</span></a> Although it is not the purpose of this paper to perform a comprehensive review on the subject&#44; we will discuss some relevant aspects&#46;</p><p id="par0525" class="elsevierStylePara elsevierViewall">The panel&#44; on the basis of available evidence does not believe that there is a need to stop BF for dental procedures in relation to the risk of osteonecrosis &#40;LE 2a&#59; DR B&#59; DA 95&#37;&#41;&#46;</p><p id="par0530" class="elsevierStylePara elsevierViewall">There have been reports of osteonecrosis of the jaw &#40;OJ&#41;&#44; but its incidence in patients with OP is very low &#40;1&#47;10<span class="elsevierStyleHsp" style=""></span>000 1&#58;100<span class="elsevierStyleHsp" style=""></span>000&#41;&#44; and it has been associated with prolonged use of BF&#46;<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">152&#44;153</span></a> Among the recommendations issued in this regard&#44; we point out those published by AEMyPS &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41;&#44; to which we refer the reader&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">154</span></a> These include a proper oral hygiene and review&#44; and if invasive dental procedures are contemplated &#40;tooth extraction or implant&#41;&#44; it is better to complete the healing process before initiating BF&#46; On the other hand&#44; there is controversy about the approach to be followed in those patients already taking BF&#46; The panel believes that discontinuation of 3&#8211;6 months should be assessed individually&#44; weighing risks and benefits&#44; since the benefit of this practice has not been evaluated scientifically&#46; It has also suggested the use of marker CTX&#44; which above a certain threshold may be associated with increased risk of OJ&#44;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">155</span></a> but there is no consistent evidence to support it&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">156</span></a></p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0535" class="elsevierStylePara elsevierViewall">Attention should be paid to the occurrence of thigh pain&#44; especially in patients with prolonged treatment with BF&#44; and X-rays used to rule out stress fractures &#40;and try to prevent progress&#41; or identify atypical fractures &#40;LE 2a&#59; DR B&#59; DA 95&#37;&#41;&#46;</p><p id="par0540" class="elsevierStylePara elsevierViewall">There have been reports of atypical fractures &#40;subtrochanteric&#47;femur shaft&#41;&#44; with a very low incidence &#40;although it could be underestimated&#41;&#46; They are usually bilateral&#44; often accompanied of pain of the thighs and&#47;or groin&#44; and are sometimes associated with some comorbidities and&#47;or medications such as HRT&#44; proton pump inhibitors or glucocorticoids&#46;<a class="elsevierStyleCrossRefs" href="#bib0785"><span class="elsevierStyleSup">157&#8211;159</span></a></p><p id="par0545" class="elsevierStylePara elsevierViewall">There is an association between the development of atrial fibrillation and the use of intravenous zoledronate&#46; There are isolated cases of esophageal cancer in patients taking oral BF&#44; though this association has not been confirmed&#46; Musculoskeletal pain&#44; kidney damage and hepatotoxicity associated to BF are exceptional and rarely cause drug withdrawal&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">160</span></a></p><p id="par0550" class="elsevierStylePara elsevierViewall">If significant adverse events occur with the use of BF&#44; the panel recommended suspending BF and evaluating the start of a drug with a different mechanism of action &#40;LE 5&#59; DR D&#59; DA 95&#37;&#41;&#46;</p><p id="par0555" class="elsevierStylePara elsevierViewall">If adverse events are significant&#44; such as OJ&#44; occur and although there is no scientific evidence indicating that the withdrawal of the drug improves the outcome of the process&#44; it is prudent to suspend and evaluate the indication of drugs with different mechanisms of action from BF&#46;</p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Denosumab</span><p id="par0560" class="elsevierStylePara elsevierViewall">Denosumab may be recommended as first-line therapy for the treatment of postmenopausal OP with risk of fracture &#40;LE 1b&#59; DR A&#59; DA 95&#37;&#41;&#46;</p><p id="par0565" class="elsevierStylePara elsevierViewall">Denosumab is a monoclonal antibody that inhibits the formation&#44; activation and survival of osteoclasts&#46; It is therefore&#44; an antiresorptive drug approved for the treatment of postmenopausal OP with a high risk of fracture&#44; at a dose of 60<span class="elsevierStyleHsp" style=""></span>mg&#47;6 months subcutaneously<a class="elsevierStyleCrossRefs" href="#bib0805"><span class="elsevierStyleSup">161&#44;162</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><p id="par0570" class="elsevierStylePara elsevierViewall">Denosumab has been reported to reduce the risk of new vertebral fractures by 68&#37; compared to placebo after 3 years of treatment &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;32&#44; 95&#37;&#44; 0&#46;26&#8211;0&#46;41&#41;&#44; the risk of hip fractures in 40&#37; &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;60&#44; 95&#37; CI&#44; 0&#46;37&#8211;0&#46;97&#41;&#44; non-vertebral fractures by 20&#37; &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;80&#44; 95&#37; CI&#44; 0&#46;67&#8211;0&#46;95&#41; and multiple fractures &#40;&#8805;2&#41;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">163</span></a> &#40;see <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46; Its effect is reversible since the inhibition that occurs in bone resorption disappears rapidly as serum levels decline&#46;<a class="elsevierStyleCrossRefs" href="#bib0820"><span class="elsevierStyleSup">164&#44;165</span></a> It is effective in patients previously treated with alendronate&#44; even without a rest interval&#44;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">166</span></a> and reduced levels of biomarkers of bone turnover&#44; particularly resorption markers&#44; fall faster and more intensely than with alendronate&#46;<a class="elsevierStyleCrossRefs" href="#bib0835"><span class="elsevierStyleSup">167&#44;168</span></a> It also produces marked increases in BMD at the lumbar spine&#44; total hip and femoral neck&#44; distal radius and total body&#44; from 12 months of treatment onward&#44; with an effect greater than alendronate and far superior to placebo&#46;<a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">163&#44;164&#44;167&#8211;171</span></a></p><p id="par0575" class="elsevierStylePara elsevierViewall">The overall incidence of adverse events was similar to placebo in terms of general infections&#44; cancer&#44; hypocalcemia and cardiovascular events&#44;<a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">163&#44;164&#44;167&#8211;170</span></a> but described a slight increase in urinary tract and skin infections<a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">163&#44;172</span></a> &#40;see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p></span></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Anabolic Drugs</span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Parathyroid Hormone Analogs</span><p id="par0580" class="elsevierStylePara elsevierViewall">PTH analogs can be recommended as first-line drugs for the treatment of OP with a high risk of fracture &#40;LE 1b&#59; DR A&#59; DA 90&#37;&#41;&#46;</p><p id="par0585" class="elsevierStylePara elsevierViewall">PTH&#39;s osteoforming<a class="elsevierStyleCrossRefs" href="#bib0865"><span class="elsevierStyleSup">173&#44;174</span></a> effects can prolong the life of osteoblasts&#44; whether administered complete<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">175</span></a> or as an amino fraction&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">176</span></a> There are two molecules on the market &#40;see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#58; teriparatide &#40;Trp&#41; or 1&#8211;34 rhPTH used at doses 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day subcutaneously&#44; and the rhPTH 1&#8211;84 &#40;PTH 1&#8211;84&#41; at doses of 100<span class="elsevierStyleHsp" style=""></span>mg&#47;day subcutaneously&#46; They are&#44; therefore&#44; osteoforming drugs whose effect is primarily anabolic&#46; The main difference is that Trp pharmacokinetics are found elevated within 3<span class="elsevierStyleHsp" style=""></span>h&#44; while the PTH 1&#8211;84 lasts up to 9<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRefs" href="#bib0885"><span class="elsevierStyleSup">177&#44;178</span></a></p><p id="par0590" class="elsevierStylePara elsevierViewall">PTH 1&#8211;34 reduces the incidence of vertebral and nonvertebral fractures but not hip fractures&#44; both as monotherapy and associated with HRT&#46;<a class="elsevierStyleCrossRefs" href="#bib0895"><span class="elsevierStyleSup">179&#44;180&#44;181</span></a> PTH 1&#8211;84 shows effectiveness in reducing vertebral fractures in women with and without previous fracture&#46;<a class="elsevierStyleCrossRef" href="#bib0910"><span class="elsevierStyleSup">182</span></a> Both are superior to alendronate in increasing BMD<a class="elsevierStyleCrossRefs" href="#bib0915"><span class="elsevierStyleSup">183&#8211;186</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;</p><p id="par0595" class="elsevierStylePara elsevierViewall">There is a limit of the duration of therapy to 2 years&#44; both for Trp as for PTH 1&#8211;84&#44; due to the occurrence of osteosarcomas in Fischer rats treated with Trp<a class="elsevierStyleCrossRefs" href="#bib0895"><span class="elsevierStyleSup">179&#44;187</span></a> for 2 years&#44; although in humans this association is not proven&#46;<a class="elsevierStyleCrossRefs" href="#bib0940"><span class="elsevierStyleSup">188&#8211;190</span></a></p><p id="par0600" class="elsevierStylePara elsevierViewall">Adverse reactions generally are not serious with either drug&#46; Mainly hypercalcemia and hypercalciuria<a class="elsevierStyleCrossRefs" href="#bib0885"><span class="elsevierStyleSup">177&#8211;179&#44;182&#44;191&#44;192</span></a> occur&#44; so it is advisable to monitor the levels of calcium in blood and urine in patients starting treatment&#46; This monitoring of serum and urinary calcium during treatment is necessary only with PTH 1&#8211;84&#46; For more information&#44; see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46;</p></span></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mixed Action Drugs</span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Strontium Ranelate</span><p id="par0605" class="elsevierStylePara elsevierViewall">Strontium ranelate &#40;RSR&#41; may be recommended as a first-line drug for the treatment of postmenopausal OP to reduce the risk of vertebral&#44; non-vertebral and hip fractures in a subgroup at high risk &#40;&#62;70 years and femoral neck DXA T &#8804;3&#41; &#40;LE 1b&#59; DR A&#59; DA 90&#37;&#41;&#46;</p><p id="par0610" class="elsevierStylePara elsevierViewall">RSR produces increased bone formation and decreased resorption in moderation&#44; which translates into an actual increase in bone mass and strength&#46;<a class="elsevierStyleCrossRefs" href="#bib0965"><span class="elsevierStyleSup">193&#8211;195</span></a> It is indicated for the treatment of OP in postmenopausal women &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><p id="par0615" class="elsevierStylePara elsevierViewall">BMD increased from 12&#46;7&#37; to 14&#46;4&#37; in the lumbar spine&#44; 5&#46;7&#37; to 8&#46;2&#37; in the femoral neck and 7&#46;1&#37; to 9&#46;8&#37; in the total hip&#46;<a class="elsevierStyleCrossRefs" href="#bib0980"><span class="elsevierStyleSup">196&#44;197</span></a> However&#44; some of this increase is due to the deposition of strontium in bone&#44; so the increase is 50&#37; of what is referred&#46; This effect is maintained for 5 years&#46;<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">198</span></a> RSR reduces vertebral fractures by 41&#37; &#40;effect detected in the first year&#41;&#44; not 16&#37; vertebral&#44; non-vertebral fractures by 19&#37; higher and hip fractures by 36&#37; in a high-risk subgroup after 3 years of treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46; This benefit remains up to 8 years afterward&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">199</span></a></p><p id="par0620" class="elsevierStylePara elsevierViewall">Although the possibility of an increased tendency for deep vein thrombosis and pulmonary embolism exists&#44; it is not clearly demonstrated&#46;<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">200</span></a> The data sheet recommends caution in patients at risk for these events&#46; There have also been cases reported of DRESS syndrome<a class="elsevierStyleCrossRefs" href="#bib1005"><span class="elsevierStyleSup">201&#44;202</span></a> and&#44; although very rare&#44; it is recommended that patients be informed to discontinue treatment if a rash appears and seek medical attention&#46; The rest of the adverse events are generally mild and transient<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">203</span></a> &#40;see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p></span></span></span><span id="sec0185" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Drugs in Development</span><p id="par0625" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a> shows the drugs that can potentially increase the currently available arsenal against OP&#46; Antiresorptive drug development is more advanced than that of anabolic drugs&#46;</p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><p id="par0630" class="elsevierStylePara elsevierViewall">Some seem to inhibit cathepsin K&#44; whose main function is to degrade bone matrix&#44; rapidly&#44; selectively and reversibly<a class="elsevierStyleCrossRefs" href="#bib1020"><span class="elsevierStyleSup">204&#8211;206</span></a>&#58; odanacatib and MK-0674&#46;<a class="elsevierStyleCrossRef" href="#bib1035"><span class="elsevierStyleSup">207</span></a></p><p id="par0635" class="elsevierStylePara elsevierViewall">Also in development are drugs capable of inhibiting integrins&#44;<a class="elsevierStyleCrossRef" href="#bib1040"><span class="elsevierStyleSup">208</span></a> Src kinase<a class="elsevierStyleCrossRef" href="#bib1045"><span class="elsevierStyleSup">209</span></a> or interfere with the acidification process &#40;chloride channel&#44; vacuolar ATP-ase&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1050"><span class="elsevierStyleSup">210</span></a></p><p id="par0640" class="elsevierStylePara elsevierViewall">Developing anabolic drugs act on two regulatory elements of osteoblastic activity&#58; the Wnt signaling pathway and activins&#46;<a class="elsevierStyleCrossRefs" href="#bib1055"><span class="elsevierStyleSup">211&#8211;217</span></a></p></span><span id="sec0190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Combination and Sequential Therapy</span><p id="par0645" class="elsevierStylePara elsevierViewall">We recommend antiresorptive therapy is instituted at the end of the 24 months cycle of anabolic drug administration and it is not recommended concomitantly with BF &#40;LE 1b&#59; DR A&#59; DA 100&#37;&#41;&#46;</p><p id="par0650" class="elsevierStylePara elsevierViewall">PTH analogs may be administered sequentially with bone resorption inhibitors or mixed-acting drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0900"><span class="elsevierStyleSup">180&#44;181&#44;184&#44;218&#8211;222</span></a> However&#44; the use of raloxifene or estrogen<a class="elsevierStyleCrossRefs" href="#bib0900"><span class="elsevierStyleSup">180&#44;181&#44;220</span></a> does not seem to inhibit their action&#46; The fact of having received prior treatment with antiresorptive does not appear to alter the anabolic effect of Trp&#46;<a class="elsevierStyleCrossRefs" href="#bib1115"><span class="elsevierStyleSup">223&#44;224</span></a></p><p id="par0655" class="elsevierStylePara elsevierViewall">Combined treatment with antiresorptives cannot be recommended across the board&#44; although their use might be justified in highly selected cases &#40;LE 5&#59; DR D&#59; DA 85&#37;&#41;&#46;</p><p id="par0660" class="elsevierStylePara elsevierViewall">Multiple associations were tested&#58; etidronate and estrogen&#44;<a class="elsevierStyleCrossRef" href="#bib1125"><span class="elsevierStyleSup">225</span></a> alendronate&#44;<a class="elsevierStyleCrossRef" href="#bib1130"><span class="elsevierStyleSup">226</span></a> risedronate<a class="elsevierStyleCrossRef" href="#bib1135"><span class="elsevierStyleSup">227</span></a> or Trp&#44;<a class="elsevierStyleCrossRefs" href="#bib0900"><span class="elsevierStyleSup">180&#44;221</span></a> raloxifene plus alendronate&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">109</span></a> Trp<a class="elsevierStyleCrossRef" href="#bib1140"><span class="elsevierStyleSup">228</span></a> or PTH &#40;1&#8211;84&#41; with raloxifene<a class="elsevierStyleCrossRefs" href="#bib0920"><span class="elsevierStyleSup">184&#44;218</span></a> and Trp&#46;<a class="elsevierStyleCrossRef" href="#bib1100"><span class="elsevierStyleSup">220</span></a> The combined administration of these drugs achieved&#44; in most cases&#44; a greater increase in BMD than monotherapy&#44; but there is no clear evidence that it improves anti-fracture efficacy&#46; Only the concomitant use of estrogen and Tpr has shown a significant reduction of new vertebral fractures&#46;<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">180</span></a> However&#44; combinations of these drugs are well-tolerated and no adverse effects could be seen on bone tissue&#46;</p></span><span id="sec0195" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What Patients Should Undergo Drug Treatment&#63;</span><p id="par0665" class="elsevierStylePara elsevierViewall">Initiate pharmacological treatment &#40;LE 5&#59; DR D&#59; DA 74&#37;&#41;&#58;<span class="elsevierStyleVsp" style="height:0.5px"></span></p><p id="par0670" class="elsevierStylePara elsevierViewall">1&#46; Postmenopausal women&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8211;</span><p id="par0675" class="elsevierStylePara elsevierViewall">Low-trauma fracture intensity&#44; regardless of the value of BMD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8211;</span><p id="par0680" class="elsevierStylePara elsevierViewall">OP &#40;BMD below &#8722;2&#46;5 SD in the <span class="elsevierStyleItalic">T</span>-score of the spine and&#47;or femur&#41; with or without fractures&#44; assessing risk factors&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8211;</span><p id="par0685" class="elsevierStylePara elsevierViewall">The use of FRAX algorithm<span class="elsevierStyleSup">A</span> may help in decision making when considering the establishment of drug treatment&#46;</p></li></ul></p><p id="par0690" class="elsevierStylePara elsevierViewall">Evaluate pharmacologic treatment&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8211;</span><p id="par0695" class="elsevierStylePara elsevierViewall">Early menopause &#40;&#60;45 years&#41; by DXA and&#47;or other risk factors&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8211;</span><p id="par0700" class="elsevierStylePara elsevierViewall">Osteopenia &#40;BMD between &#8722;1 and &#8722;2&#46;5 SD on the <span class="elsevierStyleItalic">T</span>-score&#41; Treatment is reserved for very specific cases&#44; as would be intense osteopenias near the OP range in younger women with high risk factors for fracture&#46;</p></li></ul></p><p id="par0705" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the most important risk factors<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#59; some may be by themselves an indication for treatment&#44; such as administration of glucocorticoids in doses higher than 5<span class="elsevierStyleHsp" style=""></span>mg&#47;day for over 3 months&#46;</p></span><span id="sec0200" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">How Long Should Treatment Be Maintained and How Does One Assess its Effectiveness&#63;</span><p id="par0710" class="elsevierStylePara elsevierViewall">Treatment of OP&#44; unless contraindicated&#44; should be maintained for years &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p><p id="par0715" class="elsevierStylePara elsevierViewall">The two PTH analogs can be administered only for 24 months&#46; The rest have maintained their efficacy and safety for varying periods&#58; 10 years for alendronate&#44; risedronate and etidronate up to 7 years ibandronate 3 years&#44;<a class="elsevierStyleCrossRefs" href="#bib0695"><span class="elsevierStyleSup">139&#44;148</span></a> raloxifene 8 years&#44;<a class="elsevierStyleCrossRef" href="#bib1145"><span class="elsevierStyleSup">229</span></a> zoledronate 6 years&#44;<a class="elsevierStyleCrossRef" href="#bib1150"><span class="elsevierStyleSup">230</span></a> calcitonin 5 years&#44;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">107</span></a> denosumab 3 years&#44;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">163</span></a> and rSr 8 years&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">199</span></a> We must remember that there have been reports of atypical fractures with prolonged treatment with BF&#46;<a class="elsevierStyleCrossRef" href="#bib1155"><span class="elsevierStyleSup">231</span></a></p><p id="par0720" class="elsevierStylePara elsevierViewall">Anti-osteoporotic drugs reduce but do not eliminate the risk of new fractures&#44; so that treatment can be effective even though the patient has new fractures&#46;</p><p id="par0725" class="elsevierStylePara elsevierViewall">It is recommended to assess response to treatment by central DXA every 2&#8211;3 years regardless of the type of drug &#40;LE 5&#59; DR D&#59; DA 75&#37;&#41;&#46;</p><p id="par0730" class="elsevierStylePara elsevierViewall">At the beginning of treatment it may be desirable to repeat a central DXA at one year and&#44; in situations of high risk for fracture such as transplanted patients&#44; high dose steroids and multiple vertebral fractures&#44; every 6 or 12 months &#40;LE 5&#59; DR D&#59; DA 75&#37;&#41;&#46;</p><p id="par0735" class="elsevierStylePara elsevierViewall">Bone turnover markers may be useful to assess the effectiveness of early treatment and to help improve its persistence &#40;LE 2c&#59; DR C&#59; DA 80&#37;&#41;&#46;</p><p id="par0740" class="elsevierStylePara elsevierViewall">It is recommended to evaluate the therapeutic response to anti-osteoporotic drugs with central DXA&#44; taking into account the characteristics of each patient&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23&#44;232&#8211;235</span></a> Bone turnover markers may be useful to assess its early efficacy&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;24</span></a></p><p id="par0745" class="elsevierStylePara elsevierViewall">The appearance of new fractures with a decrease in BMD values over 2&#37;&#44; which corresponds to the minimum significant change after at least one year of treatment&#44; may be seen as an inadequate therapeutic response&#46; If there is only one of those two situations&#44; the response is probably inadequate&#46; By contrast&#44; an appropriate response to treatment will be defined by the absence of these negative circumstances&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0205" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What Is the Most Appropriate Anti-osteoporotic Drug&#63;</span><p id="par0750" class="elsevierStylePara elsevierViewall">The selection of a specific drug for a patient with OP should be based on&#58; &#40;a&#41; evidence of efficacy in patients with the same characteristics&#44; &#40;b&#41; absence of contraindications&#44; &#40;c&#41; real possibility of compliance&#59; &#40;d&#41; adverse events&#44; and &#40;e&#41; efficiency of prescription&#46;</p><p id="par0755" class="elsevierStylePara elsevierViewall">Efficiency should be considered as a requirement in its entirety and not just by the price of the drug&#44; given that factors such as costs associated with its administration or affect its anti-fracture effectiveness reflect on treatment costs&#46; The prescription must be viable and take into account other associated treatments and empower the patient to achieve optimal compliance&#46;</p><p id="par0760" class="elsevierStylePara elsevierViewall">The patient must be informed to participate in decisions making regarding the selection of a particular drug &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p></span></span><span id="sec0210" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Male Osteoporosis</span><p id="par0765" class="elsevierStylePara elsevierViewall">In the male&#44; the densitometic diagnostic approach of OP is the same as in women &#40;LE 5&#59; DR D&#59; DA 95&#37;&#41;&#46;</p><p id="par0770" class="elsevierStylePara elsevierViewall">OP is a common male problem&#44; and has a similar or higher morbidity than in women&#46; The prevalence of densitometry OP in Spanish men &#62;20 years of age is estimated between 2&#46;5&#37; and 4&#46;2&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib1180"><span class="elsevierStyleSup">236&#44;237</span></a> that of radiographic vertebral fractures is 20&#37; in men &#60;65 years and in 25&#37; &#62;65 years&#44;<a class="elsevierStyleCrossRef" href="#bib1190"><span class="elsevierStyleSup">238</span></a> and the incidence of hip fracture is 73&#8211;115&#47;100<span class="elsevierStyleHsp" style=""></span>000 inhabitants &#62;50 years&#46;<a class="elsevierStyleCrossRefs" href="#bib1195"><span class="elsevierStyleSup">239&#44;240</span></a> However&#44; its diagnostic suspicion is usually low&#44; unless there are clear risk factors &#40;steroids&#44; chronic liver disease&#44; chronic obstructive pulmonary disease&#44; etc&#46;&#41;&#46;</p><p id="par0775" class="elsevierStylePara elsevierViewall">In males&#44; it is advisable to perform a basic study of the most common causes of secondary OP through a clinical history and the required laboratory tests &#40;LE 5&#59; DR D&#59; DA 100&#37;&#41;&#46;</p><p id="par0780" class="elsevierStylePara elsevierViewall">There are differences in etiopathogenesis<a class="elsevierStyleCrossRef" href="#bib1205"><span class="elsevierStyleSup">241</span></a> and in risk factors between men and women&#46; Secondary OP is more common in males&#46;<a class="elsevierStyleCrossRefs" href="#bib1205"><span class="elsevierStyleSup">241&#8211;244</span></a> In Spain&#44; the most common cause is hypogonadism &#40;10&#37;&#8211;20&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib1210"><span class="elsevierStyleSup">242</span></a> followed by chronic corticosteroid therapy and alcohol abuse&#44; usually associated with liver disease&#46;<a class="elsevierStyleCrossRefs" href="#bib1225"><span class="elsevierStyleSup">245&#44;246</span></a></p><p id="par0785" class="elsevierStylePara elsevierViewall">In the treatment of male OP the same general measures as in women&#44; and the use of drugs approved for this purpose are recommended &#40;LE 5&#59; DR D&#59; DA 75&#37;&#41;&#46;</p><p id="par0790" class="elsevierStylePara elsevierViewall">Currently&#44; drugs that have indications for male OP are risedronate&#44;<a class="elsevierStyleCrossRef" href="#bib1235"><span class="elsevierStyleSup">247</span></a> zoledronate<a class="elsevierStyleCrossRef" href="#bib1240"><span class="elsevierStyleSup">248</span></a> and Trp&#44;<a class="elsevierStyleCrossRef" href="#bib1245"><span class="elsevierStyleSup">249</span></a> with the same dosage and schedule as in female OP&#46;</p><p id="par0795" class="elsevierStylePara elsevierViewall">It is recommended that monitoring&#44; evaluation and duration of treatment be the same as in female OP &#40;LE 5&#59; DR D&#59; DA 95&#37;&#41;&#46;</p></span><span id="sec0215" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Premenopausal Osteoporosis</span><p id="par0800" class="elsevierStylePara elsevierViewall">In premenopausal women&#44; the diagnostic criteria differ according to DXA&#46; Thus&#44; the value of BMD should be applied using the <span class="elsevierStyleItalic">Z</span> scale and the diagnosis of &#8220;low bone mass&#8221; is set if <span class="elsevierStyleItalic">Z</span> scale &#60;&#8722;2 SD&#46; The presence of fragility fractures&#44; particularly associated with low bone mass&#44; allows the diagnosis of OP &#40;LE 5&#59; DR D&#59; DA 87&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib1250"><span class="elsevierStyleSup">250&#44;251</span></a></p><p id="par0805" class="elsevierStylePara elsevierViewall">About 50&#37; of cases are associated processes&#44; and a comprehensive study is recommended to identify the underlying cause &#40;LE 5&#59; DR D&#59; DA 91&#37;&#41;&#46;</p><p id="par0810" class="elsevierStylePara elsevierViewall">The most common causes are glucocorticoid treatment or Cushing&#39;s disease&#44; pregnancy&#44; osteogenesis imperfecta or estrogen deficiency&#44; anorexia nervosa and&#47;or intestinal malabsorptive diseases&#46; In addition&#44; it is known that idiopathic forms are frequent associated with hypercalciuria and a family history of OP&#46;</p><p id="par0815" class="elsevierStylePara elsevierViewall">The therapeutic approach includes an adequate intake of calcium and vitamin D&#44; exercise&#44; avoidance of tobacco and alcohol&#44;<a class="elsevierStyleCrossRef" href="#bib1260"><span class="elsevierStyleSup">252</span></a> and treating the underlying cause&#46;</p><p id="par0820" class="elsevierStylePara elsevierViewall">In patients who only show a decrease in BMD with no other risk factors&#44; pharmacologic intervention is usually not required&#44; although it is advisable to monitor these patients &#40;LE 5&#59; DR D&#59; DA 96&#37;&#41;&#46;</p><p id="par0825" class="elsevierStylePara elsevierViewall">Drug therapy is considered in specific cases such as in patients with fractures or in those with associated factors&#44; especially treatment with glucocorticoids and hypogonadism&#46; In these cases&#44; BF&#44; estrogen&#44; calcitonin&#44; PTH treatment or Trp may be indicated&#46;</p><p id="par0830" class="elsevierStylePara elsevierViewall">BF in women of childbearing potential should be used with caution&#44; as there is few data on its safety &#40;LE 5&#59; DR D&#59; DA 96&#37;&#41;&#46;</p><p id="par0835" class="elsevierStylePara elsevierViewall">Therefore&#44; contraceptive measures should be indicated in patients undergoing such treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;253</span></a></p></span><span id="sec0220" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Glucocorticoid-induced Osteoporosis</span><p id="par0840" class="elsevierStylePara elsevierViewall">Glucocorticoids &#40;GC&#41; are the most common cause of secondary OP&#44; representing up to 25&#37; of all cases of OP&#46;<a class="elsevierStyleCrossRef" href="#bib1270"><span class="elsevierStyleSup">254</span></a> It is also estimated that fractures occur in one third of those treated after one year and 50&#37; at some point in their evolution&#46;<a class="elsevierStyleCrossRef" href="#bib1275"><span class="elsevierStyleSup">255</span></a></p><p id="par0845" class="elsevierStylePara elsevierViewall">The risk of fracture caused by GC depends on several factors&#58; BMD at the beginning of treatment&#44; daily and accumulated dose&#44; and underlying disease&#46; BMD loss is rapid&#44; especially during the first year&#44; even at low doses&#44; and trabecular bone is most affected&#46;<a class="elsevierStyleCrossRef" href="#bib1280"><span class="elsevierStyleSup">256</span></a> There are individual characteristics that make these patients more vulnerable to lower doses of corticosteroids and develop osteoporosis more than others with higher doses&#46;<a class="elsevierStyleCrossRef" href="#bib1285"><span class="elsevierStyleSup">257</span></a> Due to the great changes that occur on the bone microarchitecture&#44; fractures produced by GC appear with BMD values that are higher than in other types of OP&#44; so that the threshold for intervention should be located above the <span class="elsevierStyleItalic">T</span>-score of postmenopausal OP&#46;</p><p id="par0850" class="elsevierStylePara elsevierViewall">The prevention and treatment of OP should begin as soon as possible&#46; Preventive measures should be undertaken in patients using doses equivalent to &#8805;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day of prednisone for more than 3 months&#46; If there is a history of fragility fractures or the patient is over 65&#44; the start of drug treatment is recommended&#46; In those that do not have fractures and are less than 65 years old&#44; a DXA is indicated and if this presents a <span class="elsevierStyleItalic">T</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#8722;1&#46;5 SD&#44; drug treatment is indicated&#46;<a class="elsevierStyleCrossRef" href="#bib1290"><span class="elsevierStyleSup">258</span></a></p><p id="par0855" class="elsevierStylePara elsevierViewall">Preventive measures&#58; in patients who are to take prolonged GC the following should be considered&#58; &#40;a&#41; use the lowest GC dose possible and as suspend it as quickly as possible&#44; &#40;b&#41; avoidance of the use of tobacco&#47;alcohol&#44; a balanced diet with adequate calcium intake&#44; etc&#46;&#44; &#40;c&#41; prevention of muscle loss and falls with a program of proper nutrition and exercise&#44; &#40;d&#41; supplementation with calcium and vitamin D &#40;LE 5&#59; DR D&#59; DA 90&#37;&#41;&#46;</p><p id="par0860" class="elsevierStylePara elsevierViewall">Drug therapy&#58; BF &#40;alendronate&#44; risedronate or zoledronate&#41; and Trp have proven effective in the prevention and treatment of OP due to GC&#46;<a class="elsevierStyleCrossRefs" href="#bib1290"><span class="elsevierStyleSup">258&#8211;267</span></a> All treatments should always be supplemented with adequate doses of calcium and vitamin D&#46; In patients at a high risk of fracture&#44; treatment may be started with osteoforming agents &#40;Trp&#41; followed by BF&#46; Treatment with thiazides &#40;25<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; should be considered in patients with hypercalciuria&#46;</p><p id="par0865" class="elsevierStylePara elsevierViewall">According to technical data&#44; drugs for corticosteroid associated OP are Trp&#44; risedronate and zoledronate &#40;see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p></span></span><span id="sec0225" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0870" class="elsevierStylePara elsevierViewall">As commented in the introduction&#44; the objective of this document is to update on advances in the different clinical aspects of osteoporosis&#58; diagnosis&#44; evaluation&#44; follow up and treatment&#46; This has been a joint effort by members of the panel and the RU of SER and has entailed a large systematic review on different topics of interest and has provided the necessary scientific strength to emit recommendations with a degree of evidence but also of consensus&#44; providing the reader a more objective evaluation of these recommendations&#46;</p><p id="par0875" class="elsevierStylePara elsevierViewall">This paper highlights a number of new contributions in the field and the inclusion of some tables that complement the various recommendations&#46; On the one hand&#44; we have expanded the areas of clinical interest with pre-menopausal osteoporosis&#44; male osteoporosis and osteoporosis secondary to steroids&#46; Furthermore&#44; we have added two new antiresorptive drugs&#58; bazedoxiphen and denosumab&#46; We have also included the results of systematic reviews aimed at answering the following questions&#58; the relationship of biphosphonates to osteonecrosis of the jaw and atypical fractures of the femur&#44; the relationship between calcium supplementation and the occurrence of kidney stones&#44; and the degree of evidence of different algorithms to calculate the risk of fracture&#46; And finally&#44; we have joined the tables that summarize the effectiveness of different drugs in reducing fractures and current approved indications &#40;data sheets&#41;&#44; dosage&#44; adverse events and interactions with other drugs&#46;</p><p id="par0880" class="elsevierStylePara elsevierViewall">It is also important to emphasize some observations in this document&#46; The first is the fact that the evaluation of the risk for fracture was one of the topics that generated a greater debate among the panel members&#44; because it had been intended that the same criteria as previous documents or the FRAX<span class="elsevierStyleSup"><span class="elsevierStyleBold">&#169;</span></span> algorithm were to be used&#46; The panel&#39;s solution was to expose both options so that the reader may have the largest information possible and so that it may help in identifying patients at risk for osteoporosis&#46;</p><p id="par0885" class="elsevierStylePara elsevierViewall">The degree of evidence of the different drugs is based on its &#8220;main studies&#8221; and in most of them the primary objective was the reduction in vertebral fractures&#44; noting that the efficacy in the reduction of non-vertebral and hip fractures does not represent the same degree of evidence&#46; Only rSr and risedronate have carried out studies in which the primary objective has been non-vertebral and hip fractures&#44; respectively&#46;</p><p id="par0890" class="elsevierStylePara elsevierViewall">As stated in this document and&#44; according to the European Drug Agency&#44; indications for the use of bazedoxiphen and denosumab are for women with high risk of fracture&#44; contrasting with the analysis of their main studies which were based in populations with a majority of patients without previous fracture&#44; making them moderate in risk&#46; It is necessary to take this into account when choosing appropriate treatment&#46;</p><p id="par0895" class="elsevierStylePara elsevierViewall">In conclusion&#44; the recommendations of this document constitute a background for management of OP&#46; They are general norms that must be individualized in a role we&#44; as professionals&#44; must assume&#46;</p></span><span id="sec0230" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Disclosures</span><p id="par0900" class="elsevierStylePara elsevierViewall">The authors have no disclosures to make&#46;</p></span></span>"
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            ]
            2 => array:2 [
              "identificador" => "sec0210"
              "titulo" => "Male Osteoporosis"
            ]
            3 => array:2 [
              "identificador" => "sec0215"
              "titulo" => "Premenopausal Osteoporosis"
            ]
            4 => array:2 [
              "identificador" => "sec0220"
              "titulo" => "Glucocorticoid-induced Osteoporosis"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0225"
          "titulo" => "Discussion"
        ]
        8 => array:2 [
          "identificador" => "sec0230"
          "titulo" => "Disclosures"
        ]
        9 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2011-05-03"
    "fechaAceptado" => "2011-05-20"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec112893"
          "palabras" => array:4 [
            0 => "Consensus"
            1 => "Guidelines"
            2 => "Osteoporosis"
            3 => "Recommendations"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec112892"
          "palabras" => array:4 [
            0 => "Consenso"
            1 => "Gu&#237;a"
            2 => "Osteoporosis"
            3 => "Recomendaciones"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Due to increasing improvement in the diagnosis&#44; evaluation and management of osteoporosis and the development of new tools and drugs&#44; the Spanish Society of Rheumatology &#40;SER&#41; has promoted the development of recommendations based on the best evidence available&#46; These recommendations should be a reference to rheumatologists and other health professionals involved in the treatment of patients with osteoporosis&#46;</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Recommendations were developed following a nominal group methodology and based on a systematic review&#46; The level of evidence and the degree of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford&#46; The level of agreement was established through Delphi technique&#46; Evidence from previous consensus and available clinical guidelines was used&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We have produced recommendations on diagnosis&#44; evaluation and management of osteoporosis&#46; These recommendations include the glucocorticoid-induced osteoporosis&#44; premenopausal and male osteoporosis&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We present the SER recommendations related to the biologic therapy risk management&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Dado el creciente avance en el diagn&#243;stico como evaluaci&#243;n y tratamiento de la osteopososis&#44; y la incorporaci&#243;n de nuevas herramientas y medicamentos&#44; desde la Sociedad Espa&#241;ola de Reumatolog&#237;a &#40;SER&#41; se ha impulsado el desarrollo de recomendaciones basadas en la mejor evidencia posible&#46; Estas deben de servir de referencia para reumat&#243;logos y otros profesionales de la salud implicados en el tratamiento de pacientes con osteoporosis&#46;</p> <span class="elsevierStyleSectionTitle">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Las recomendaciones se emitieron siguiendo la metodolog&#237;a de grupos nominales&#46; El nivel de evidencia y el grado de recomendaci&#243;n se clasificaron seg&#250;n el modelo del Center for Evidence Based Medicine de Oxford y el grado de acuerdo se extrajo por t&#233;cnica Delphi&#46; Se utiliz&#243; toda la informaci&#243;n de consensos previos y gu&#237;as de pr&#225;ctica cl&#237;nica disponibles&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se realizan recomendaciones sobre el diagn&#243;stico&#44; evaluaci&#243;n y tratamiento en pacientes con osteoporosis&#46; Estas recomendaciones incluyen la osteopososis secundaria a glucocorticoides&#44; la osteoporosis premenop&#225;usica y la del var&#243;n&#46;</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se presentan las recomendaciones SER sobre el diagn&#243;stico&#44; evaluaci&#243;n y manejo de pacientes con osteoporosis&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please&#44; cite this article as&#58; P&#233;rez Edo L&#44; et al&#46; Actualizaci&#243;n 2011 del consenso Sociedad Espa&#241;ola de Reumatolog&#237;a de osteoporosis&#46; Reumatol Clin&#46; 2011&#59;<span class="elsevierStyleBold">7&#40;6&#41;</span>&#58;357&#8211;79&#46;</p>"
      ]
    ]
    "multimedia" => array:7 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High risk &#40;&#8805;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">1&#46;</span> Advanced age &#40;65 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">2</span>&#46; Low weight &#40;BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">3</span>&#46; Personal history of fractures&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">4</span>&#46; Maternal history of fractures&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">5</span>&#46; Steroids<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">6</span>&#46; Falls<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate risk &#40;&#62;1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">7</span>&#46; Tobacco and&#47;or alcohol consumption<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">8</span>&#46; Early menopause &#40;45 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">9</span>&#46; Primary and secondary amenorrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">10</span>&#46; Hypogonadism in the male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">11</span>&#46; Diseases and drugs with a capacity to reduce BMD&#58; rheumatoid arthritis and other inflammatory arthropathies&#44; inflammatory intestinal disease&#44; celiac disease&#44; malabsorption&#44; liver disease&#44; hyperparathyroidism&#44; hyperthyroidism&#44; anorexia and bulimia&#44;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> patients with solid organ transplants&#44; use of hydantoin&#44; antiretrovirals&#44; antiepileptics&#44; etc&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">12</span>&#46; Factors related to falls&#58; visual disturbances&#44; psychopharmacology&#44; stroke&#44; Parkinson&#39;s disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab212116.png"
              ]
            ]
          ]
          "notaPie" => array:4 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara">More than 5<span class="elsevierStyleHsp" style=""></span>mg&#47;prednisone&#47;day for over 3 months&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara">More than 2 falls in the past year&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara">Tobacco use and alcohol consumption &#62;3 units a day&#58; one unit of alcohol is equivalent to 8&#8211;10<span class="elsevierStyleHsp" style=""></span>g&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara">If untreated it may be considered as a risk factor for fracture&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Risk Factors for Fracture&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">CF&#58; Femoral neck&#59; DMO&#58; Bone densitometry&#59; F&#58; femoral fracture&#59; FT&#58; total femur&#59; FV&#58; vertebral fracture&#59; H&#58; humeral fracture&#59; CRF&#58; chronic renal failure&#59; MP&#58; postmenopausal women&#59; ND&#58; no defined&#47;no determined&#59; NV&#58; non-vertebral fracture&#59; OP&#58; osteoporosis&#59; R&#58; fracture of the distal third of the radius&#59; US&#58; ultrasound&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="17" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Fracture Risk Scales &#40;1&#44; 2&#44; 3&#41;</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Fracture&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Catalan Agency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">EPESE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Minimal Data Group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Community of Madrid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">D&#237;ez&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">WHI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">NORA</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Garvan Institute</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">FRAX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Qfracture&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Body Weight<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">ABONE<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">ORAI<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">DOE Score<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Year</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2009&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1996&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Reference</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#44; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#44; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#44; 17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Population</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MP<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>65 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8805;65 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MP<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>50 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MP<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>65 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MP 50&#8211;79 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MP 50&#8211;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8805;60 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&#8211;90 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#8211;85 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>50 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Time limit&#44; years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 and 10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Fracture evaluated</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&#44; V&#44; NV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&#44; all&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">All&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&#44; V&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">All&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Weight&#47;height&#47;BMI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#40;FT&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">US&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">X<a class="elsevierStyleCrossRef" href="#tblfn0065"><span class="elsevierStyleSup">i</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Markers of bone remodeling</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Health habits&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Previous fracture&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Protein rich diet&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Poor physical activity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Activities of daily living&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cognitive alterations&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Self assessed health&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Urinary incontinence&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Falls&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Visual acuity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Walking speed&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Difficulty getting up&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Falls in the previous year&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="18" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Family history of fracture</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">X<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">X<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">X<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">X<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hormonal status&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hypogonadism&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Early menopause&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Amenorrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Prior use of estrogens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&#46; of offspring&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">OP secondary to disease</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Chronic hepatitis&nbsp;\t\t\t\t\t\t\n