( PDF ) Rev Osteoporos Metab Miner. 2018; 10 (1) Supplement: 13-17
DOI: 10.4321/S1889-836X2018000200004

Sosa Henríquez M1,2, Gómez de Tejada Romero MJ1,3
1 Universidad de Las Palmas de Gran Canaria – Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBM) – Grupo de investigación en osteoporosis y metabolismo mineral – Las Palmas de Gran Canaria (España)
2 Hospital Universitario Insular – Unidad Metabólica Ósea – Las Palmas de Gran Canaria (España)
3 Universidad de Sevilla – Departamento de Medicina – Sevilla (España)

 
 

Introduction
Fracture fractures are the only clinical complication of osteoporosis1-3. Therefore, treatment should be aimed at preventing the appearance of fractures, since they are associated with an increase in morbidity and mortality4,5. In this sense, the presence of fragility fractures is a cause for alarm and treatment needs to be established as early as possible. It is wrong to think that when we treat a fractured patient we have arrived late and that it is not cost-beneficial to start treatment, because, on the one hand, having suffered a fragility fracture is a risk factor for a new fracture and on the other hand, the establishment of treatment for osteoporosis not only reduces the risk of new fractures, but also decreases the mortality of patients who have suffered them5,6.

 

The osteoporosis treatment pyramid
Figure 1 shows the “osteoporosis treatment pyramid”7. Treatment should commence by indicating a series of general non-pharmacological measures, summarized in table 1. These measures have been shown to be effective in reducing the risk of the appearance of fragility fractures8,9. From the moment osteoporosis is diagnosed, patients who smoke should be advised to stop smoking, and all those who carry out load-bearing physical exercise, according to their physical state (walking being the simplest and the first that should indicate), recommending to do it for 1 hour a day, which can be fractioned8,10. Patients who have appropriate physical condition can dance or practice activities in a gym, such as Tai-Chi 11 or Pilates12 if they choose. Weight-lifting exercises should be avoided, especially those involving flexion of the spine due to the risk of vertebral fracture.

Patients are instructed to maintain a balanced, healthy diet, which must include dairy products12. Depending on weight and lipid metabolism, dairy products can be taken in skim or whole form, since the amount of calcium is the same, differing only in levels of fat. It is a mistake to restrict or eliminate dairy products from the diet, as it leads to the development of a negative balance in calcium metabolism and the production of secondary hyperparathyroidism, which worsens osteoporosis12. Before starting treatment with osteoporosis drugs, it is advisable that patients visit their dentist to check their mouth and resolve any pathology that may require further surgical manipulation: extractions, de-vitalizations, implants, etc. Thus, one of the most important risk factors in the appearance of maxillary osteonecrosis (ONJ), may be eliminated13,14.
Most fragility fractures occur as a result of a fall and, therefore, it is advisable at the time of gaining clinical history data, to ascertain whether patients are suffering from repeated falls and to find out the possible causes15, to act on them as much as possible. In this sense it should be taken into account that most of the falls are usually produced inside the house and, in it, in the bathroom. Polypharmacy, so prevalent among the elderly, must also be monitored and, on occasion, it can condition an increased risk of falls16.

 

Is it necessary to administer calcium and vitamin D?
Yes, for several reasons. First and foremost, because all the reference studies conducted to establish the risk reduction of fragility fractures have been carried out by administering a supplement of calcium and vitamin D7 to the patients. If we want to obtain the same results for which the drug was approved for use in patients, we should, if possible, try to reproduce the same clinical conditions as in the study. Second, most patients with osteoporosis and fragility fractures have hypovitaminosis D and do not ingest the recommended amounts of calcium by consensus17. Finally, although controversial, calcium and vitamin D supplementation may have a certain beneficial effect in reducing the risk of new fractures, especially in the hip and in patients with previous hypovitaminosis14-17. without forgetting that vitamin D supplements have been shown to be effective in reducing the risk of falls15,16. For all these reasons, it is advisable to administer 1,000 IU/day of vitamin D3 and 600 mg/day of calcium to all patients under treatment for osteoporosis18-20.

 

Which drug to choose? Are they all the same?
The drug should be chosen according to the circumstances of each patient, once we have made the complete clinical assessment and diagnosed osteoporosis1,7,21,22. In principle, we should use a drug that reduces the risk of suffering any fracture: vertebral, non-vertebral and hip, but at this time in the vademecum of our country we have only 4 drugs that meet this requirement: alendronate, risedronate, zoledronate, and denosumab7,22. Strontium ranelate has recently been withdrawn from the market as well as calcitonin and other bisphosphonates (etidronate, pamidronate and ibandronate), selective modulators of estrogen receptors (SERMs) and the two parathormones (teriparatide and intact PTH) which do not reduce the risk of fracture of the femur (Table 2).

As indicated in another study of this collection, there is agreement in practically all the national and international therapeutic guidelines to consider alendronate and risedronate as the primary drugs of choice in osteoporosis treatment7,22-26.
Although it reduces the risk of all fragility fractures, zoledronate is administered iv and its use is reserved for the hospital setting, which is why it is considered a second-choice drug 7,22. Denosumab must also be administered by injection, subcutaneously, and is also considered a second-choice drug22,26.
Teriparatide and, within SERMs, bazedoxifene are drugs to be taken into account in certain circumstances. Thus, if the patient presents vertebral fractures at the time of diagnosis or presents very low BMD levels, two-year treatment with teriparatide could begin, which is allowed by the health authorities26. Once finished, another drug should be continued. It has been reported that after suspending teriparatide, the addition of a bisphosphonate prolonged the beneficial effect in reducing the risk of fracture29 although there is a certain residual effect28.
Bazedoxifene can be used as an alternative to alendronate and risedronate, when these cannot be used for any reason7,22,26, but its clinical spectrum is totally opposite to teriparatide, since it would be indicated in patients with a lower risk of hip fracture26.
Denosumab is a potent antiresorptive that completely reduces fragility fracture risk30. In all therapeutic guidelines, it is considered a second-line drug and alternative to alendronate and risedronate7,21-26,31,32. On the one hand, it is to be administered parenterally every other year. On the other hand, at its price that almost triples the annual cost of alendronate27 and, finally, because several articles have recently been published that show that, if patients are not strictly compliant, or if the drug is discontinued, there may be a notable loss of previously obtained BMD and an alarming increase in the incidence of new vertebral fractures33,34. This may already be observed 6 months after suspending the drug, which in clinical practice is equivalent to forgetting a dose.
In a recent meta-analysis, it was concluded that the best initial treatment for postmenopausal osteoporosis, in terms of cost-effectiveness, is alendronate or zoledronate, both generic 31.

 

How long should treatment with a drug be maintained?
The so-called therapeutic holidays
Most studies conducted to assess the efficacy and safety of drugs used in the treatment of osteoporosis have been designed with a follow-up of 3 years. Exceptionally, five-year follow-ups have been carried out with calcitonin and strontium ranelate (remarkably, both drugs have been withdrawn from the pharmaceutical market because of their side effects). We have observational data after a few years follow-up of the cohorts of the original studies on alendronate and risedronate, and six-year data with zoledronate35. The best long-term data collected are those obtained by the study conducted with denosumab, which lasted up to 10 years.
All of them have shown that the beneficial effect on the reduction of the risk of fracture is maintained during this time, and that in the case of some bisphosphonates there is a beneficial “residual” effect that is maintained even after the drug has been suspended, specifically for alendronate, risedronate and zoledronate35.
In recent years, a current of opinion has developed which suggests that, in patients treated with bisphosphonates over a certain number of years, suspension should be considered to avoid two possible complications. These are osteonecrosis of the maxillary and atypical fractures or diaphyseal fractures21,35-37. This conclusion has been shared and recommended by several major scientific societies, because in these patients, studying the clinical factors associated with the appearance of these complications, bisphosphonate use for more than five years could be one of the causes22,35-40.
It is a controversial issue, with discrepancies41. We believe that the so-called therapeutic holidays, (simply suspending treatment), are indicated to patients who tolerate the drug well, which is being effective in reducing the risk of fracture and that has not produced any side effects and has forced its withdrawal. Bisphosphonate is suspended on a preventive basis in these patients before possible complications, which have not yet occurred. The risk of these complications is very low, clearly lower than the risk that patients have of suffering a fragility fracture for which the drug was indicated. Therefore, our opinion is that as long as the patient tolerate the treatment well and no reasons have been identified to suspend the drug due to side effects or intolerance, it should be continued as long as possible40. In addition, as the years of treatment with the drug go by, the patient increases in age, which is one of the main risk factors for fragility fracture.

 

Conclusion
The treatment of osteoporosis should be directed mainly at the secondary prevention of fractures. The appearance of adverse effects related to drugs for the osteoporosis treatment has made medical professionals re-evaluate the indications, the time of treatment and even withdraw the commercialization of some of them.
General non-pharmacological measures should be observed, the risk of falls assessed and calcium and vitamin D supplemented in all cases.
In general, antiresorptive drugs (alendronate and risedronate) are considered the first choice. Zoledronate or denosumab are second-line drugs and will be indicated in cases of digestive intolerance, poor adherence or an increased risk of hip fracture. Teriparatide will be indicated in patients with 2 or more previous vertebral fractures or with very low bone density.

Conflict of interests: The authors declare no conflict of interests.

 

 

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