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 (LE 5; DR D; DA 100%).

Bone resistance reflects the integration of bone density and bone quality. At the same time, bone density is determined by the peak value of bone mass and the magnitude of its loss, while bone quality depends on architecture, bone exchange, the accumulation of microlesions and mineralization.2

There is no current population survey protocol that is universally accepted for the identification of persons with OP. 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.3

In certain groups of patients, mainly the elderly and postmenopausal women, we must maintain a high degree of suspicion and actively search for risk factors (LE 5; DR D; DA 100%).

An osteoporotic fracture or fragility fracture is conditioned by low impact trauma. A fall from a standing or sitting position is included in this concept. Fractures that occur as a consequence of sports or accidents are excluded (LE 5; DR D; DA 100%).

It is estimated that close to 40% of Caucasian women will have at least one fracture after the age of 50.4–9 The most frequent and relevant are those of the proximal femur, the spinal column and the distal forearm. On the other hand, we must point out that fractures of the cranium or face are excluded from this definition.10

As occurs with OP, there is no universally accepted survey to identify the population with a high risk of fracture.

The risk of osteoporotic fracture is determined by the presence of one or more risk factors including low bone mineral density (BMD). The combination of risk conferred by a low BMD with clinical risk factors11 allows for a better estimate of risk. We consider a high risk for fracture when there are at least 2 high risk factors (Table 1). 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.

Different instruments that estimate the risk of fracture based on risk factors have been developed (Table 2). Of them, the most important is the FRAX tool©, a software tool sponsored by the WHO,12 which can be applied with and without BMD. The FRAX® algorithms calculate the absolute 10 year probability of fracture into a group of “major fractures” (clinical vertebral, forearm, hip and humeral fractures) and isolated hip fractures. It is currently the most recommended instrument used to calculate the risk of osteoporotic fracture. However, as everything, it has limitations and the medical judgment of the clinician is still fundamental. The risk of a major fracture calculated by FRAX© in the Spanish population over 15% is very specific for osteoporosis.

There is no consensus in the medical literature on the threshold above which the risk for a fracture would be considered “high” in the Spanish population. An approximation would be:

• –

  Absolute 10 year risk of fracture <10%: low.

• –

  Absolute 10 year risk of fracture ≥10% and <20%: moderate.

• –

  Absolute 10 year risk of fracture ≥20%: low.

If FRAX© is employed, its systemic application is recommended in patients in whom: (a) the indication of a BMD is being evaluated; (b) the onset of treatment is being evaluated for OP, and (c) they are over 65 years of age.

If OP is suspected, with the aim of evaluating the risk of fracture and the cause of OP, we recommend obtaining the following data: age, ethnicity, history of toxic habits (tobacco, alcohol), dietary intake of calcium and vitamin D, degree of exposure to sunlight, menstrual history (age at menopause and menarche), obstetric history (interventions, surgical menopause, hypogonadism), osteopenia associated diseases and drugs, previous trauma, family or personal history of fragility fractures and conditions associated to falls, as well as data regarding recent or prior fractures (LE 5; DR D; DA 95%).

The presence of present or prior fractures should be evaluated determining episodes of acute and/or chronic back pain, progressive reduction in height, etc.13,14 It is important to remember that OP is asymptomatic and that more than half of the vertebral fractures are also asymptomatic.15

It is recommended that physical examination record weight, height, the existence of skeletal deformities and palpation/percussion of the spine be carried out (LE 5; DR D; DA 90%).

The relationship between the body mass index and BMD is well known.16 The possible existence of skeletal deformities should be established by the presence of dorsal kyphosis, a reduction of the space between the ribs and the pelvis, etc., and palpation/percussion should be directed to the localization of painful zones of the locomotor system.14 General physical examination may provide data on other diseases associated to a reduction in bone mass.

Laboratory tests are performed to identify associated processes and perform a differential diagnosis with other diseases associated to bone fragility.17–21

When OP is suspected, one should request: complete blood count, alkaline phosphatase, creatinine, serum proteins, erythrocyte sedimentation rate, serum calcium and phosphorus and 24h urinary calcium excretion (LE 5; DR D; DA 100%).

It is advisable to determine during the initial visit what the levels of 25-hydroxyvitamin D (25-[OH]-D3), parathyroid hormone (PTH) and thyroid stimulating hormone are (LE 5; DR D; DA 80%).

In case an associated disease is suspected, pertinent laboratory tests should be performed (LE 5; DR D; DA 95%).

The systematic determination of bone markers is not recommended for the diagnosis and evaluation of patients with OP. Their measurement is useful to identify subjects with a greater risk of fracture and especially to evaluate in an early manner response to, both antiresorptive as well as bone forming treatments (LE 2c; DR C; DA 80%).

Bone remodeling markers provide additional and complementary information to the study of BMD. Osteocalcin, bone alkaline phosphatase and type I procollagen aminoterminal propeptide stand out as bone formation markers and pyridinolynes, carboxy and aminoterminal telopeptides of type I collagen (serum CTX and urine NTX) and tartrate 5b resistant acid phosphatase stand out among those associated to resorption. These are more sensitive and specific than classic markers such as total alkaline phosphatase and hydroxyproline. 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.22–24

Spine radiographs are not useful to assess the decrease in BMD, but allow the diagnosis of fractures, including asymptomatic ones. We must remember that the presence of prior vertebral fracture is a significant risk factor for new fractures, both vertebral and non-vertebral.25–29

In patients with suspected or diagnosed OP, it is recommended to perform an initial spinal X-ray for detecting fractures (LE 2b; DR B; DA 95%).

If there is suspicion of vertebral fracture during follow up, a spinal X-ray is recommended (LE 2b; DR B; DA 100%).

The panel believes that for the diagnosis of spinal fractures, lateral, dorsal and lumbar spine X-rays, with focus on D8 and L2, respectively30 are sufficient (LE 2a; DR C; DA 100%).

Anteroposterior projections are not essential for diagnosis but can provide additional information.

A densitometric survey of the general population is not cost-effective31 and there is great variability regarding indications for densitometry.3,32–37 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. The evaluation of BMD along with other risk factorsis useful for the diagnosis and follow up of patients.

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 (LE 2b; DR B; DA 95%).

Before requesting for it is essential to be certain that the result will help determine the therapeutic decision to be taken.38

A baseline densitometry is recommended in the following (LE 5; DR D; DA 75%):

• 1.

  Women with early menopause and any major risk factors for fracture.

• 2.

  Postmenopausal women of any age and men over 50 with at least one major risk factor for fracture.

• 3.

  A history of fragility fracture in patients over 50.

• 4.

  Underlying disease or chronic treatment with medication associated to bone loss, especially glucocorticoids.

• 5.

  Women over 65 years of age and men >70 without known risk factors at least in one occasion if patient request it.

• 6.

  Evaluation of pharmacologic treatment.

• 7.

  If the FRAX© is employed, a densitometry is recommended in women 65 and older and those younger but with a major risk factor for fracture according to the FRAX©, equivalent to a 65 year old woman with no risk factors de riesgo (Spanish FRAX 3.6%).39,40

To detect significant changes with a confidence interval (CI) of 95%, these should be, at least, 2.8 times the variation coefficient (minimum significant change). In clinical practice its application is difficult because very strict precision measures are needed.41 The use of another concept is more practical, “the smallest detectable difference” which is established in 2% (change in lumbar BMD±0.05g/cm2, total femur±0.04g/cm2).42 Although major changes in BMD are detected on the lumbar spine, it is also useful to monitor the hip because it is less dependent on artifacts produced by degenerative change.

Dual energy X-ray absorciometry (DXA) is recommended as the reference technique for measuring BMD (LE 2b; DR B; DA 100%).

DXA is a technique that has good precision, low radiological exposure and allows for measurement of BMD both in the axial as well as in the peripheral skeleton. It is considered the best technique to evaluate BMD.28,41,42

Results of BMD obtained through DXA predict the future risk of fracture due to OP, both in postmenopausal women as in elderly males.43–49 But in addition, according to WHO, to diagnose OP it is necessary to know the value of the BMD in the femur and lumbar spine through a central DXA.50,51 Currently, central DXA is the only validated technique to follow up and for evaluation of therapeutic response.

To perform a diagnosis of OP, we recommend carrying out a DXA, as long as it is possible on the hip and lumbar spine (LE 2b; DR B; DA 95%).

A lateral projection of the spine should not be used for the diagnosis of OP.

If DXA of the lumbar spine or hip is impossible, it is recommended that DXA be performed on the distal third of the radius of the non-dominating forearm (LE 2b; DR B; DA 90%).

This may occur in case of anatomical alterations (scoliosis, degenerative problems, multiple vertebral fractures, morbid obesity) or technical problems (presence of metallic elements after spinal surgery, hip arthroplasty).52

When necessary, control DXA of the hip and the spine should be performed with the same equipment (LE 1b; DR A; DA 90%).

Long-term precision or reproducibility of DXA; expressed as a variation coefficient, varies according to the measurement area and the equipment used from 1 to 2%.53–55 In women undergoing treatment for postmenopausal OP, densitometric controls should be performed every 2–3 years.32 In general, 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.55

Ultrasound, 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, follow up or evaluation of therapeutic response in patients with OP (LE 1a; DR A; DA 95%).

There are other techniques to measure BMD in the peripheral skeleton, such as phalangeal, knee and calcaneus DXA, and calcaneus ultrasound. They are cheaper, easier to handle and faster in comparison to central DXA but, among other limitations, their precision is low.49,52,56,57 They are useful to predict the future risk of fracture and may have some value when it is impossible to perform a central DXA.49,52,56 Peripheral quantitative computed tomography is a rapidly developing imaging technique. It allows for volumetric BMD measurement of the lumbar spine, hip and distal radiums, but its results are not comparable to those obtained through DXA.58

Diagnosis of OP is based on the densitometric criteria established by WHO for white postmenopausal women (BMD values under −2.5 standard deviations (SD) (T-score inferior to −2.5) and/or the presence of fragility fractures (LE 2c; DR B; DA 90%).

Cutpoints for BMD measured by DXA on the lumbar spine and hip59–61 correspond to normal, values of BMD>−1 SD in relation with the mean of young adults (T-score>−1); osteopenia or low bone mass, BMD values between −1 and −2.5 SD (T-score between −1 and −2.5); OP, BMD values of <−2.5 DE (T-score<−2.5), and established OP when the previous condition is associated to ≥1 osteoporotic fracture. The same cutpoints have been proposed for adult males.60

The following general measures should be recommended to all of the population, with special emphasis on osteoporotic patients: physical exercise, elimination of toxic habits, balanced diet, adequate intake of calcium and vitamin D, preventing falls (LE 1a; DR A; DA 100%).

Moderate to intense physical exercise increases bone mass in young patients,62–66 as well as in adults, although less intensely.67 There is no consistent evidence on the effect over bone mass in elderly patients, but performing it reduces the risk of fractures, probably by reducing falls.68–70

Avoidance of sedentarism and the performance of moderate physical activity are recommended, taking into account the patients’ age, physical status and other diseases (LE 5; DR D; DA 100%).

A balanced diet with an adequate consumption of proteins, avoidance of excess salt and moderate sun exposure are also recommended (LE 5; DR D; DA 100%).

A daily calcium intake of 1000mg and serum 25-OH vitamin D levels of ≥30ng/ml (75mmol/l) is recommended (LE 5; DR D; DA 100%).

Sometimes, common diets do not provide these calcium requirements and therefore must be modified or supplemented with pharmacological calcium which, if taken isolatedly, has not shown a significant effect on the reduction of fractures in postmenopausal OP, but help reduce the loss of bone mass.71–73 In healthy women it has been suggested to increase cardiovascular risk74,75 and renal litiasis,76 but this is a controversial and unclear subject.

Approximately 50% of the osteoporotic population presents low serum concentrations of vitamin D and it is advisable to supplement it with 800–1000U in all patients. The efficacy of vitamin D supplements in the prevention of fractures is controversial.77–82 There is evidence that it reduces fractures in institutionalized elderly patients when administered with calcium.77–82 Additionally, some studies indicate that vitamin D supplements may reduce falls81 but other do not.82

In patients receiving anticatabolic treatment, we recommend an intake of 1000mg of calcium and 800–1000U of vitamin D is recommended (LE 1a; DR A; DA 95%).

In the elderly, measures directed at reducing the risk of falls, promoting the use of canes, avoiding psychopharmacologic agents, correcting visual disturbances and adapting living spaces are recommended. In high risk populations, hip protectors may be employed.83–85

For more information consult Table 3.

The goals of treatment of a vertebral fracture are acute pain control and functional recovery (LE 2b; DR B; DA 100%).

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.86

Oral analgesics, relative rest, orthoses and rehabilitation are the mainstays of treatment (LE 2b; DR B; DA 90%).

Oral analgesics are first-line drugs to reduce the pain of vertebral fractures. The choice should be appropriate to the magnitude of pain. In cases where the pain reaches a significant intensity and conventional painkillers failed, we recommend using opioids.87,88

If complete rest is indicated, return to sitting and walking should be accomplished in the shortest possible time. During the acute episode there may be a need for prescription orthotics and, once control of acute pain is achieved, rehabilitation may be useful (LE 5; DR B; DA 95%).

A back brace should be used with caution as excessive spinal immobility could increase OP,89 and rehabilitation should be directed by a specialist.90

In patients with acute vertebral fractures with pain that does not respond to the above measures, vertebroplasty or kyphoplasty may be indicated (LE 1c; DR B; DA 95%).

Several observational studies have shown rapid analgesic effect and reduced period of immobilization in a high percentage of patients, in the short to medium term, but this does not exempt these procedures from secondary.91–96 Recently, two controlled clinical trials have not shown that vertebroplasty was more effective than other conservative options.97,98 Another controlled trial has found benefit with the use of vertebroplasty in a subgroup of patients with persistent intense symptoms.99 Based on the above, patients who are going to undergo these interventions should be carefully selected.100

Currently, no generalization can be recommended for vertebroplasty or kyphoplasty to treat osteoporotic vertebral fractures (LE 5; DR D; DA 100%).

The objective of pharmacologic treatment of OP is to reduce the risk of fracture (LE 1a; DR A; DA 100%).

Pharmacological intervention is performed with therapeutic agents capable of acting in both phases of bone remodeling. At present, there are three categories of anti-osteoporotic drugs, antiresorptive and anti-catabolic, which inhibit bone resorption by acting on osteoclasts and their precursors, decrease the rate of activation of bone remodeling, increase bone mineral density and preserve the microarchitecture of the bone; and anabolic drugs, which act on osteoblasts or their precursors resulting in increased bone remodeling, with bone formation increased to a greater extent than resorption, which in time increases mass and bone strength, as well as agents with a double mechanism of action where there is a combination of both.101,102

For more information regarding their indications, efficacy in relation to the prevention of fractures and adverse events, see Tables 4 and 5.

Table 7 shows the drugs that can potentially increase the currently available arsenal against OP. Antiresorptive drug development is more advanced than that of anabolic drugs.

Some seem to inhibit cathepsin K, whose main function is to degrade bone matrix, rapidly, selectively and reversibly204–206: odanacatib and MK-0674.207

Also in development are drugs capable of inhibiting integrins,208 Src kinase209 or interfere with the acidification process (chloride channel, vacuolar ATP-ase).210

Developing anabolic drugs act on two regulatory elements of osteoblastic activity: the Wnt signaling pathway and activins.211–217

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 (LE 1b; DR A; DA 100%).

PTH analogs may be administered sequentially with bone resorption inhibitors or mixed-acting drugs.180,181,184,218–222 However, the use of raloxifene or estrogen180,181,220 does not seem to inhibit their action. The fact of having received prior treatment with antiresorptive does not appear to alter the anabolic effect of Trp.223,224

Combined treatment with antiresorptives cannot be recommended across the board, although their use might be justified in highly selected cases (LE 5; DR D; DA 85%).

Multiple associations were tested: etidronate and estrogen,225 alendronate,226 risedronate227 or Trp,180,221 raloxifene plus alendronate,109 Trp228 or PTH (1–84) with raloxifene184,218 and Trp.220 The combined administration of these drugs achieved, in most cases, a greater increase in BMD than monotherapy, but there is no clear evidence that it improves anti-fracture efficacy. Only the concomitant use of estrogen and Tpr has shown a significant reduction of new vertebral fractures.180 However, combinations of these drugs are well-tolerated and no adverse effects could be seen on bone tissue.

Initiate pharmacological treatment (LE 5; DR D; DA 74%):

1. Postmenopausal women:

• –

  Low-trauma fracture intensity, regardless of the value of BMD.

• –

  OP (BMD below −2.5 SD in the T-score of the spine and/or femur) with or without fractures, assessing risk factors.

• –

  The use of FRAX algorithmA may help in decision making when considering the establishment of drug treatment.

Evaluate pharmacologic treatment:

• –

  Early menopause (<45 years) by DXA and/or other risk factors.

• –

  Osteopenia (BMD between −1 and −2.5 SD on the T-score) Treatment is reserved for very specific cases, as would be intense osteopenias near the OP range in younger women with high risk factors for fracture.

Table 1 shows the most important risk factors12; some may be by themselves an indication for treatment, such as administration of glucocorticoids in doses higher than 5mg/day for over 3 months.

Treatment of OP, unless contraindicated, should be maintained for years (LE 5; DR D; DA 100%).

The two PTH analogs can be administered only for 24 months. The rest have maintained their efficacy and safety for varying periods: 10 years for alendronate, risedronate and etidronate up to 7 years ibandronate 3 years,139,148 raloxifene 8 years,229 zoledronate 6 years,230 calcitonin 5 years,107 denosumab 3 years,163 and rSr 8 years.199 We must remember that there have been reports of atypical fractures with prolonged treatment with BF.231

Anti-osteoporotic drugs reduce but do not eliminate the risk of new fractures, so that treatment can be effective even though the patient has new fractures.

It is recommended to assess response to treatment by central DXA every 2–3 years regardless of the type of drug (LE 5; DR D; DA 75%).

At the beginning of treatment it may be desirable to repeat a central DXA at one year and, in situations of high risk for fracture such as transplanted patients, high dose steroids and multiple vertebral fractures, every 6 or 12 months (LE 5; DR D; DA 75%).

Bone turnover markers may be useful to assess the effectiveness of early treatment and to help improve its persistence (LE 2c; DR C; DA 80%).

It is recommended to evaluate the therapeutic response to anti-osteoporotic drugs with central DXA, taking into account the characteristics of each patient.22,23,232–235 Bone turnover markers may be useful to assess its early efficacy.22–24

The appearance of new fractures with a decrease in BMD values over 2%, which corresponds to the minimum significant change after at least one year of treatment, may be seen as an inadequate therapeutic response. If there is only one of those two situations, the response is probably inadequate. By contrast, an appropriate response to treatment will be defined by the absence of these negative circumstances.24

The selection of a specific drug for a patient with OP should be based on: (a) evidence of efficacy in patients with the same characteristics, (b) absence of contraindications, (c) real possibility of compliance; (d) adverse events, and (e) efficiency of prescription.

Efficiency should be considered as a requirement in its entirety and not just by the price of the drug, given that factors such as costs associated with its administration or affect its anti-fracture effectiveness reflect on treatment costs. The prescription must be viable and take into account other associated treatments and empower the patient to achieve optimal compliance.

The patient must be informed to participate in decisions making regarding the selection of a particular drug (LE 5; DR D; DA 100%).