The main risk factors are shown in Table 1. After suffering a first fracture, the greatest risk of suffering a new fracture occurs in the subsequent two years, especially if the first fracture was vertebral.2 This phenomenon led to formulating the concept of “imminent risk” of fracture.

X-ray absorptiometry (DXA), which quantifies bone mineral density (BMD), is commonly used to estimate fracture risk. The diagnosis of osteoporosis is established with a T score <−2.5 in any of the following locations: lumbar spine, total hip, or femoral neck (Table 2).

In premenopausal women and men under 50 years, the use of Z scores is recommended, with Z≤−2.0 considered “low BMD for chronological age.”

The trabecular bone score may improve the prediction of fracture risk.

In general, DXA is recommended when risk factors are strongly associated with osteoporosis or fractures (Table 1).

Radiography is essential for identifying fractures. In the case of the vertebralfractures, the diagnosis requires a decrease of at least 20–25% in height. In some cases, imaging based on DXA (i.e., vertebral fracture assessment, VFA) may be an alternative.

A complete blood count and biochemical analysis should be carried out (kidney and liver function, calcium, albumin, phosphorus, alkaline phosphatase, thyrotropin, 25-hydroxyvitamin D [25OHD], proteinogram and calciuria). The suitability of determining parathyroid hormone (PTH) and bone turnover markers (BTM) is a subject of debate. Other studies should be performed in young patients to rule out secondary causes of osteoporosis (e.g., hypercortisolism, celiac disease, and systemic mastocytosis).

DXA and evaluation of possible vertebral fractures will almost always be necessary.

Together with other risk factors, BTMs can aid in identifying patients with a higher risk of fracture and, (above all) they help early assessment of the response to treatment. The most widely used are the carboxyterminal telopeptides of type I collagen (s-CTX, Serum C-telopeptide cross-link type 1 collagen) and the amino-terminal peptides of type I procollagen (procollagen type 1 N-terminal propeptide).

A combination of clinical data and DXA is useful to assess fracture risk. Several instruments have been developed for this purpose, including FRAX, the Garvan Medical Research Institute scale, and the QFracture Index. They have a similar discriminatory capacity and are only moderately efficient. FRAX is the most widespread. Unfortunately, its adaptation to the epidemiology of fractures in Spain has been inadequate and underestimates the risk of major osteoporotic fractures.

A balanced diet should be maintained, with a contribution of 1–1.5g/kg of protein, regular physical exercise, and avoiding tobacco and excessive alcohol consumption. Fall prevention programmes and hip protectors may be helpful in some cases.

Patients treated with drugs for osteoporosis should have an adequate intake of calcium and vitamin D3,4 to attain serum levels of 25OHD>25–30ng/mL. The generally recommended dose of vitamin D is 800–1200IU/d (or weekly or monthly equivalent). If calcifediol is used, 0.266 micrograms are given every 15–30 days. Calcium intake should be 1000–1200mg/day, preferably through diet and supplements if needed.

Calcitonin, strontium ranelate, PTH 1–84, isoflavones, phytoestrogens, and tibolone are not indicated for the treatment of osteoporosis. Thiazides can be used to control hypercalciuria.

Although oestrogen therapy effectively prevents fractures, its possible side effects have prevented it from being recommended as an osteoporosis treatment, except in cases of early menopause or when other alternatives are not available.

Selective oestrogen receptor modulators (SERMs) increase spinal BMD. Raloxifene and bazedoxifene reduce vertebral fracture risk by 40% but do not influence nonvertebral fractures.5 Its main complication is an increased risk of venous thromboembolic disease.

Denosumab reduces the risk of vertebral, non-vertebral, and hip fractures by around 70%, 20%, and 40%, respectively.9

It is generally well tolerated. The risks of AFF and ONJ are very low, around 1/10,000 and 1/2000 patients/year, respectively. Denosumab can be used in patients with kidney failure, even those on dialysis. An adequate supply of calcium and vitamin D must be ensured to avoid hypocalcaemia.

After discontinuation, an increase in bone turnover markers (BTM) and a loss of BMD gained are observed. In some patients, this phenomenon is associated with multiple vertebral fractures.

Teriparatide exerts a bone-forming effect and reduces vertebral fracture risk by 65% and non-vertebral fractures by 50%. A meta-analysis did not show a significant reduction in hip fractures, but another three concluded that it reduced these fractures by 56–65%. It was shown to be more effective than risedronate in women with severe osteoporosis.10 Several biological analogues and biosimilars are marketed.

Abaloparatide reduces vertebral and non-vertebral fractures. It is approved in the US but not in Europe.

Romosozumab is a sclerostin-neutralising antibody with dual anabolic and antiresorptive effects.

According to several meta-analyses,5,11 this agent reduces vertebral (66–73%), non-vertebral (33%), and hip (56%) fractures. In women with severe osteoporosis, a cycle of romosozumab provided additional benefits to alendronate.12

Romosozumab is generally well tolerated; however, in some studies, a small increase in cardiovascular events was described (1.3% vs 0.9%); therefore, it is contraindicated in patients with a history of myocardial infarction or cerebrovascular accident and should be considered carefully in those with multiple cardiovascular risk factors.

Although many noncontrolled studies have shown a marked analgesic effect, randomised clinical trials have provided conflicting results for vertebroplasty and kyphoplasty. Thus, they are not routinely recommended.

They can be considered in patients with fractures less than 6 weeks old and severe pain despite medical treatment and in patients with fractures from 6 weeks to a year of evolution and persistent pain that responds poorly to analgesics if they show signs of oedema on MRI.

In general, patients with some of these characteristics should be treated:

• 1.

  One or more fragility fractures, especially the vertebrae, hip, humerus, and pelvis (regardless of BMD).

• 2.

  BMD<−2.5T score in the lumbar spine, femoral neck, or total hip.

• 3.

  BMD in the “osteopenia” range (particularly if T is <−2.0) together with factors strongly associated with fracture risk (e.g., hypogonadism or early menopause, treatment with glucocorticoids or antiestrogens).

Some situations require an individualised assessment of the clinical characteristics. In young women with only slightly low BMD and no fractures or other risk factors, delaying treatment can be considered because the absolute risk of fracture is low. By contrast, the coincidence of several important risk factors may lead to earlier treatment consideration. Scales that help estimate fracture risk (e.g., FRAX) may be helpful, although their validity in the Spanish population is limited.

If necessary, adherence to treatments can be monitored using BTMs, whose changes predict therapeutic response.

The beneficial effect of the treatment is confirmed by the evolution of BMD and the absence of new fractures. A change of treatment may be considered due to a possible inadequate response if two new fractures appear during treatment or two of the following events occur: a new fracture, a significant decrease in BMD (e.g., 4−5%), or a decrease of the BTM less than the minimum significant change (approximately 25%).

Several aspects must be considered. Although the treat-to-target strategy is theoretically attractive, the aims to be achieved in treating osteoporosis are not well defined, limiting its practical application. For some experts, the absence of new fractures and an increase in BMD would be the most appropriate. Various experts have recommended a T score greater than −2.0 or −2.5 as a target, especially in the hip.

Several studies demonstrated the persistence of the effect by maintaining zoledronate for 6 years or alendronate or denosumab for 10 years. However, side effects (particularly ONJ and AFF) may increase with the duration of treatment. Therefore, it is recommended to reassess patients treated with BP at 3 (zoledronate) or 5 years (oral BP) and those treated with denosumab at 5–10 years.

Treatment should be continued (with the same drug or with another) if any of the following circumstances occur:

• a.

  BMD at the femoral neck <−2.5T.

• b.

  The appearance of fragility fractures in the 3–5 years before evaluation.

• c.

  Some experts also recommend continuing treatment if the patient has a history of hip or vertebral fracture at some point in life.

If none of these circumstances occurs, treatment with BP can be withdrawn, at least temporarily (“therapeutic holidays”): for risedonate, 1 year; for alendronate, 2 years; and for zoledronate, 3 years. In the case of denosumab, temporary interruptions should not be considered.