Browse the corpus

Osteoporosis is a systemic disease of the skeleton, defined as a decrease in bone mass content and disruption of the microarchitecture of bone tissue, causing increased bone fragility. The consequence is an increased risk of fractures even with minimal trauma []. The prevalence of osteoporosis in the Slovak population in accordance with SCOPE21 is estimated at ca. 6% []. The most common sites of typical osteoporotic fractures are the distal forearm, vertebrae, and the hip. The risk of osteoporotic fracture at these sites in postmenopausal women is ca. 40 to 50%, and in older men, the risk can range from 13 to 25%. As life expectancy increases, the incidence of osteoporotic fracture may increase. These fractures occur in the absence of any apparent trauma. Mortality in patients with vertebral and proximal femur fractures is ca. 6 to 8 times higher than in the healthy population, up to 20% of proximal femur fracture patients die within 1 year of the fracture, and another 30% remain permanently immobile. Osteoporotic fractures substantial affect morbidity, mortality, and quality of life [].

Osteoporosis can be divided into primary and secondary. Primary osteoporosis Postmenopausal osteoporosis (type I) Secondary osteoporosis is mostly caused by a known disease. It includes an entire range of disease and morbid conditions that lead to changes in bone metabolism.

Its appearance is characteristic ca. 15–20 years after menopause, and trabecular bone is most affected. Estrogen deficiency is the decisive pathophysiological mechanism of postmenopausal osteoporosis. The main clinical manifestation is bone fractures with a higher proportion of trabecular bone, mainly vertebrae.

It occurs mostly in people over 70 years of age. It affects women only slightly more often than men. The most significant pathogenetic factors of senile osteoporosis include age-decreasing bone formation, circulatory and neurotrophic bone disorders, age-related structural changes in bone collagen, and secondary hyperparathyroidism with reduced calcium absorption due to reduced calcitriol formation. It is manifested by fractures, both in ​​cortical and trabecular bone, mainly fractures of the proximal femur.

It occurs in younger individuals (both men and women) without a proven connection to another underlying disease. The most common causes of secondary osteoporosis include the following: - Osteoporosis with hormone deficiency: sex hormone and growth hormone deficiency - Osteoporosis due to an excess of hormones: hypercortisolism, hyperthyroidism, hyperprolactinemia, hyperparathyroidism, and acromegaly - Osteoporosis caused by nutritional disorders - Insufficient intake of calcium, vitamin D, digestive disorders, and malabsorption syndromes - Mineral and bone disorder in chronic kidney disease–mineral and bone disorder (CKD–MBD) - Osteoporosis in chronic inflammatory diseases

A fracture is commonly the first manifestation of osteoporosis. Typical osteoporotic fractures are fractures of the proximal femur, wrist, and vertebral fractures. Vertebral fractures can occur acutely or gradually. Acutely formed fractures are manifested by sudden sharp pain; otherwise, vertebral fractures present with chronic static back pain and loss of height. Up to 2/3 of vertebral fractures may be asymptomatic. Other osteoporotic fractures are low-traumatic fractures of the humerus, pelvis, ribs, and—especially in patients with obesity and type 2 diabetes mellitus (DM)—also fractures of the distal part of the upper and lower limbs. Skull fractures and fractures of small bones of the hands and feet are not usually considered osteoporotic fractures. The uncontrollable risk factors include age, female sex, genetic predisposition, white race, slender habitus, positive family history of osteoporotic fractures, and a history of a fracture after inadequate trauma. Controllable risk factors include lifestyle factors, chronic diseases, and medications with a negative effect on bone metabolism (Table ) [].

Diagnostics and differential diagnosis are provided by a bone-focused physician specializing in the fields of rheumatology, endocrinology, orthopedics, internal medicine, gynecology, or clinical oncology. Other physicians: specialists carry out consulting activities for the needs of diagnosis, differential diagnosis, and treatment, primarily for secondary osteoporosis and other metabolic diseases of the skeleton. Diagnosis and differential diagnosis of osteoporosis consists of the following: - History-taking - Determination of fracture risk using the FRAX calculator

The aim of the history is to obtain information about the fractures overcome so far and the circumstances of their occurrence, data on fractures in family members, dietary habits with a focus on ensuring the supply of calcium and vitamin D, and data on physical activity. Considering the asymptomatic course of the disease, it is necessary to focus on the determination of osteoporosis risk factors and fracture risks (see previous section) [] and the symptoms of diseases leading to secondary osteoporosis.

In the physical examination, one should focus on the change in height (decrease in height by more than 4 cm compared with the height in youth), accentuation of thoracic kyphosis, bulging of the abdomen, low body weight (BMI: below 19 kg/m 2 ), gracile habitus, physical findings indicating for another disease that can lead to secondary osteoporosis, and a physical finding typical of another metabolic osteopathy.

The aim of the biochemical examination is as follows: - Assessment of the state of phospho-calcium metabolism. - Evaluation of the activity and speed of bone metabolism. - Differential diagnosis of secondary osteoporosis and other skeletal diseases. Basic laboratory tests in the diagnosis and differential diagnosis of osteoporosis are as follows: - Blood count - Serum calcium, phosphorus, and alkaline phosphatase - Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GMT) - Glomerular filtration (GF) and creatinine - Protein electrophoresis (ELFO) in serum and urine - Excretion of calcium and phosphates in the urine in 24 h (or their fractional excretions) - Examination of the level of 25-hydroxy vitamin D3 The reference marker of bone formation is the serum level of P1 NP (procollagen type I N propeptide), and the reference marker of bone resorption is the CTX (C-terminal cross-linking telopeptide of type I collagen). Examination of markers of bone turnover is important: - Prediction of the rate of bone mineral density (BMD) decline. - Fracture risk prediction independent of BMD. - Evaluation of the correct use of anti-osteoporotic treatment (compliance). - Assessment of the duration of the interruption of therapy (so-called drug holiday). Measurement of bone turnover markers is indicated: - Before starting anti-osteoporotic therapy.

The gold standard for measuring bone mass content is densitometry []. The principle of densitometric examination consists in measuring the degree of absorption of X-ray rays by bone tissue (RTG absorptiometry: DXA, from English dual-energy X-ray absorptiometry). Indications for the densitometric examination are in Suppl. Table . The so-called central densitometry (DXA) measures BMD in the proximal femur, lumbar spine, and forearm. In postmenopausal women and men over 50 years of age, evidence of a decrease in bone density T-score ≤ − 2.5 SD is required in at least one of the following locations: antero-posterior (AP) projection of lumbar spine or proximal femur. A T-score is a multiple of a standard deviation from the mean of a normal young healthy population. The lowest values ​​of the measured T-score are always considered. When measuring in ​​the lumbar spine, vertebrae L1 to L4 are evaluated. Vertebrae distorted by local structural changes must be excluded from the average, but at least two vertebrae must be analyzed. It is not possible to diagnose osteoporosis from the density of one vertebra. See also Suppl. Table .

In premenopausal women and men younger than 50, it is appropriate to use the Z-score for the diagnosis of osteoporosis. The Z-score is a multiple of the standard deviation from the mean of a normal healthy population of the same age and sex. Osteoporosis can be diagnosed if low BMD (Z-score ≤ − 2.0 SD) is also associated with secondary causes of osteoporosis or if an osteoporotic fracture is already present (a vertebral fracture or two peripheral fractures after inadequate trauma). The diagnosis of osteoporosis cannot be established based on DXA measurements alone, and a Z-score of ≤ − 2.0 SD alone should be evaluated only as a decrease in BMD below the expected value for the given age and not as osteopenia or osteoporosis. A Z-score above − 2.0 SD should be evaluated as a BMD value within the expected range. Measurements on the forearm can be used to diagnose osteoporosis in patients with the following: - Primary hyperparathyroidism - Extreme obesity (exceeding the limits of the densitometric table) - No measurable or evaluable region of the spine or femur To establish the diagnosis of osteoporosis, in the case of measurement on the forearm, it is necessary to evaluate the density in the area referred to as 33% radius (1/3 radius) of the non-dominant upper limb [].

Ultrasound measurement of bone density in the heel region has only predictive value for fracture risk assessment. The measurement is not suitable for establishing a diagnosis of osteoporosis. Measurement of bone density using quantitative computed tomography (QCT) densitometry can be indicated if it is not possible to perform or evaluate the measurement by central DXA, and the patient’s history and clinical manifestations strongly suspect osteoporosis with the perspective of the need for anti-osteoporotic treatment. If the probability of fracture assessed by QCT of the spine (using device-specific thresholds) together with adverse clinical risk factors is sufficiently high, the indication of pharmacological treatment can be considered as measured by the DXA method [].

A follow-up DXA study should be performed on the same device. If the device changes during the control measurement, it is not possible to evaluate the change in density without using it adequate conversion of the so-called cross-calibration. To assess the change in bone density, DXA measurement in the AP projection in ​​the lumbar spine or the area of ​​the proximal femur is recommended. The doctor should indicate the control measurement of the density at a time when it can be assumed that the change in bone density will be higher than the value of the least significant change (LSC) determined at the given workplace. Control measurement is indicated after 1 year of starting or changing anti-osteoporosis treatment. After proving the sufficient effectiveness of the applied treatment (see also the chapter on the evaluation of the effectiveness of the treatment), it is usually possible to extend the measurement interval, provided that the applied treatment is continued and the (presumed) adequate adherence of the patient to the treatment is ensured, and at the same time, the risk profile does not significantly change. If there is a reasonable assumption that a significant change in bone density will be achieved earlier than 1 year (rapid loss of bone density, e.g., in secondary osteoporosis, especially glucocorticoid-induced osteoporosis), it is possible to shorten the control measurement interval to less than 1 year. After completion or interruption of treatment, a control measurement is indicated after 18 to 36 months. Central densitometry in the forearm area—or ultrasound densitometry in the heel area—is not suitable for monitoring changes in bone density.

The evaluation of the densitometric measurement should be performed by a medical specialist with experience in the evaluation of densitometric scans based on the previous criteria. Osteoporosis is a lifelong disease with a persistent risk of fractures. Therefore, even if the T-score value improves and reaches the osteopenia or normal range during the treatment of osteoporosis, the diagnosis of osteoporosis remains [].

The quality control (QC) program should be in accordance with the manufacturer’s recommendation for system maintenance. If it is not recommended by the manufacturer, the following QC procedures are suitable: periodic (at least once per week) scanning of the phantom as an independent assessment of system calibration, printing, and analysis of data on calibration and phantom scans and verification of the average BMD of the phantom after each service intervention in the densitometer. Assessment of measurement accuracy is part of standard clinical practice. Each densitometric workplace should have its own calculated value of the minimum significant change in density, the so-called LSC, for each operator and after each device change. The measurement error specified by the manufacturer should not be used. In accordance with the ISCD, the acceptable value of the minimum significant change (i.e., the LSC) for individual sections and each operator should not be higher than 5.3% on the spine in the AP projection, higher than 5.0% in the area referred to as “total hip,” and higher than 6.9% on the neck of the femur. See also Suppl. Tables and for s pecific requirements for the densitometric evaluation reports.

Trabecular bone score (TBS) is a tool that captures information regarding the trabecular microarchitecture and thus the quality of the bone structure based on the texture of the lumbar spine scans performed using DXA. Low TBS is significantly associated with the incidence of osteoporotic fractures and is partially independent of clinical risk factors and BMD in the area of ​​the lumbar spine and proximal femur. TBS may also play a role in assessing fracture risk in some causes of secondary osteoporosis in which bone density is poorly correlated with this risk (e.g., type 2 DM, hyperparathyroidism, acromegaly, and glucocorticoid-induced osteoporosis). Using TBS to determine fracture risk based on the FRAX calculator leads to improvement of fracture prediction. TBS values are divided as follows: TBS ≥ 1.31 is considered normal; TBS from 1.23–1.31 is considered consistent with a partially degraded microarchitecture, and TBS ≤ 1.23 is defined a degraded microarchitecture []. Several diagnostic methods are used in the diagnosis and differential diagnosis of osteoporosis, which can be divided into the following: 1) Basic examinations - X-ray examination - X-ray of the Th and LS spine in a lateral projection to evaluate deformities in patients with an increased risk of vertebral fractures,

- X-ray of the skeleton (spine, pelvis, skull, upper limbs, and lower limbs) in the diagnosis of fractures and in the differential diagnosis of other skeletal diseases. - Computed tomography (CT) and magnetic resonance (MR) examination. The diagnosis of osteoporosis can be established if a low-traumatic fracture of the vertebra or proximal femur is present (independent of BMD). The diagnosis of osteoporosis can be established if the measured T-score value is from − 1.0 to − 2.5 SD and at the same time: - Low-traumatic fracture of the proximal humerus, pelvis, or distal forearm. - Multiple low-traumatic fractures in other places (except the face, feet, and hands). Low-traumatic (osteoporotic) fractures can be considered those that occurred without known trauma or after an inadequately small trauma (this can be defined as a fall from a height no higher than a fall from a standing position). When evaluating a fracture, it is therefore necessary to take the mechanism of the injury into account [].

The classification of fractures in the spine is based on the assessment of changes in the height of the Th and LS vertebral bodies in the lateral projection using the semi-quantitative method in accordance with Genant []. The method will also enable the classification of vertebral fractures. A reduction in the height of the vertebral body by more than 20% (anterior, posterior edge, or center) is considered a grade 1 fracture or mild fracture. A height reduction of more than 25% and less than 40% indicates moderate fracture (grade 2 fracture). A reduction of more than 40% indicates a grade 3 fracture, or a severe fracture.

A CT or an MR examination of the spine is indicated if it is not possible to clearly detect a decrease in the height of the vertebral body from a classic X-ray examination or lateral DXA scan (e.g., scoliosis, condition after spine surgery). They are also recommended when clinical symptoms and other tests suggest that the decrease in vertebral body height may be due to a cause other than osteoporotic vertebral deformity.

FRAX is a computer algorithm that calculates the 10-year probability of any major fracture (hip, spine, humerus, or wrist) and the 10-year probability of a proximal femur fracture. Fracture risk is calculated based on age, BMI, and risk factors that include past osteoporotic fracture, family history of proximal femur fracture, smoking, long-term glucocorticoid use, rheumatoid arthritis, other causes of secondary osteoporosis, and alcohol consumption. The BMD value of the proximal femur can be added to increase fracture risk prediction. When calculating risk using FRAX, we can use three methods: - FRAX without BMD Patients with a FRAX ≥ 20% for any major osteoporotic fracture and/or a FRAX ≥ 3% for a proximal femur fracture are considered high risk []. The FRAX specific to the Slovak population is on the website: https://www.sheffield.ac.uk/FRAX/tool.aspx?country=44 .

The cause of low bone density needs to be evaluated in every patient. If—based on the history, objective findings, and the results of basic laboratory and imaging examinations—it can be assumed that low bone density, in addition to age, or other risk factors also play a role in estrogen deficiency, it is necessary to rule out secondary osteoporosis and other metabolic diseases of the skeleton, which may be accompanied by low bone density. These are mainly patients under the age of 50. In older patients, it is necessary to think about secondary osteoporosis, especially if the bone density is significantly lower than the expected value for the given age, that is, if the Z-score value is lower than − 2.0 SD and in patients with a rapid decrease in BMD. Differential diagnosis includes the exclusion of all diseases that lead to secondary osteoporosis or low bone density (Table ) with the use of all necessary laboratory and imaging methods in accordance with the assumed diagnosis. A bone biopsy is indicated if other methods cannot clarify the etiology of low density, repeated fractures, or it is necessary to exclude other metabolic or tumor involvement of the bones.

As part of the prevention of osteoporosis and osteoporotic fractures, it is necessary to exclude known risk factors (Table ), to reduce the risk of falls. Patients should be recommended a physically active lifestyle, maintaining a BMI above 19 kg/m 2 and weight-bearing exercises adapted to the needs and abilities of the patient. An adequate supply of protein in the diet is recommended. It is necessary to ensure an adequate daily intake of calcium. The recommended dose of calcium in accordance with age, gender, and hormonal status is in Suppl. Table . If it is not possible to ensure the recommended amount of calcium in the diet, supplementation in the form of calcium preparations is suitable. Vitamin D supplementation is recommended for patients with a proven vitamin D deficiency as well as for people with a presumed deficiency (elderly patients, especially with insufficient exposure to sunlight and in the winter months). The goal of supplementation is to ensure an optimal level of 25-OH-D3 vitamin (≥ 30 ng/mL or ≥ 75 nmol/L). The recommended daily dose of cholecalciferol is 800 to 1000 IU (see also Suppl. Table ). In patients with chronic kidney disease, the administration of vitamin D analogues is an alternative [] (Table ).

Secondary prevention of fractures is focused on patient care after osteoporotic fractures. Patients after treatment of an osteoporotic fracture of the forearm (after the age of 50) as well as patients with a diagnosed osteoporotic fracture of the vertebra should be referred by the attending physician (orthopedic, traumatologist, surgeon, or emergency medicine physician) for examination in the outpatient clinic of a specialist focused on diagnosis, differential diagnosis, and osteoporosis treatment [, ]. After treatment of osteoporotic fracture of the proximal femur, it is necessary to provide calcium and vitamin D supplementation during hospitalization (unless there are contraindications to their administration); and upon discharge, the patient is sent for examination in the outpatient clinic of a specialist focused on diagnosis, differential diagnosis, and treatment of osteoporosis.

The goal of osteoporosis treatment is to reduce the risk of fracture. Adequate supplementation of calcium and vitamin D is the basis of prevention and treatment. Ensuring the daily requirement of calcium and the ideal level of vitamin D is also necessary when taking antiresorptive and/or osteoanabolic treatment. The treatment is long-term, usually lifelong, considering the contraindications of this treatment. Drugs that have been proven to reduce fracture risk include antiresorptives (bisphosphonates such as alendronate, ibandronate, risedronate, and zoledronic acid, as well as denosumab and raloxifene), osteoanabolics (such as teriparatide), and mixed-action therapies (such as romosozumab) (see Table ) [].