Primary osteoporosis
(I) Definition and classification
Osteoporosis (OP) is a systemic bone disease characterized by low bone mass, destruction of bone microarchitecture, resulting in increased bone fragility and susceptibility to fracture (WHO). In 2001, the National Institutes of Health (NIH) proposed that osteoporosis is a disease of the skeletal system characterized by decreased bone strength and increased risk of fracture, and that bone strength reflects two major aspects of bone, namely bone mineral density and bone mass. Xue-Mei Li, Department of Rheumatology and Immunology, Xuanwu Hospital, Capital Medical University
The disease can occur in different genders and at any age, but is mostly seen in postmenopausal women and older men. Osteoporosis is divided into two main categories: primary and secondary. Primary osteoporosis is subdivided into three types: postmenopausal osteoporosis (type I), senile osteoporosis (type II) and idiopathic osteoporosis (including adolescent type). Postmenopausal osteoporosis generally occurs within 5-10 years after menopause in women; senile osteoporosis generally refers to osteoporosis occurring in the elderly after the age of 70; secondary osteoporosis refers to osteoporosis caused by any disease or drug affecting bone metabolism; and idiopathic osteoporosis mainly occurs in adolescents, and the etiology is unknown.
(ii) Epidemiology
Osteoporosis is a degenerative disease with an increased risk of developing with age. A large national epidemiological survey in 2003-2006 showed that the total prevalence of osteoporosis based on vertebral and femoral neck BMD values over the age of 50 was 20.7% in women and 14.4% in men. The prevalence of osteoporosis is significantly higher in people over 60 years of age, especially in women. It is estimated that the rate of hip fracture in Chinese people will increase significantly in the coming decades. The lifetime risk of osteoporotic fracture in women (40%) is higher than the combined risk of breast, endometrial, and ovarian cancers.
A serious consequence of osteoporosis is the occurrence of osteoporotic fractures (fragility fractures), which are fractures that can occur with minor trauma or during daily activities. The common sites of osteoporotic fractures are the spine, the hip, and the distal forearm. It is important to emphasize that osteoporotic fractures are preventable and treatable. Early prevention can prevent osteoporosis and its fractures. Even if a fracture has occurred, the risk of re-fracture can still be effectively reduced with appropriate and reasonable treatment. Therefore, it is important to popularize the knowledge of osteoporosis, to achieve early diagnosis, to predict the risk of fracture in time and to take standardized prevention and treatment measures.
II. Clinical manifestations
Pain, spinal deformation and fragility fracture are the most typical clinical manifestations of osteoporosis.
Patients may have low back pain or circumferential skeletal pain, and the pain may increase when the load increases or the activity is limited, and in severe cases, there are difficulties in turning, sitting and walking.
Severe osteoporosis may result in height shortening and hunchback, spinal deformity and limited extension. Compression fractures of the thoracic spine can lead to thoracic deformity and affect cardiopulmonary function. Fractures of the lumbar spine may alter abdominal anatomy and cause constipation, abdominal pain, bloating, decreased appetite and a feeling of premature fullness.
A fragility fracture is a low-energy or nonviolent fracture, such as a fracture that occurs as a result of daily activities. Common sites are the thoracic and lumbar spine, the hip, the distal radius and ulna, and the proximal humerus. Fractures can also occur at other sites. After a fragility fracture has occurred, the risk of another fracture increases significantly.
III. Risk factors and risk assessment of osteoporosis
(A) Risk factors for osteoporosis
1 Inherent factors: ethnicity (Caucasians and yellow people have a higher risk of osteoporosis than blacks), old age, female menopause, maternal family history.
2 Non-inherent factors: low body weight, low sex hormones, smoking, excessive alcohol consumption, excessive coffee consumption, lack of physical activity, nutritional imbalance in the diet, too much or not enough protein, high sodium diet, calcium and/or vitamin D deficiency (low light exposure or low intake), presence of diseases affecting bone metabolism and application of drugs affecting bone metabolism.
(ii) Risk assessment of osteoporosis
There are many clinical methods to assess the risk of osteoporosis, and two simple assessment methods with high sensitivity and easy operation are recommended here as screening tools.
1 International Osteoporosis Foundation (IOM) Osteoporosis 1-minute test questions
(1) Have you ever injured your bones from a minor bump or fall?
(2) Have your parents ever had a hip fracture after a minor bump or fall?
(3) Do you regularly take hormonal drugs such as cortisone and prednisone for more than 3 months in a row?
(4) Has your height decreased by more than 3 cm from your youth?
(5) Do you regularly drink a lot of alcohol?
(6) Do you smoke more than 20 cigarettes a day?
(7) Do you often have diarrhea? (caused by gastrointestinal diseases or enteritis)
(8) Ms. answer: Did you become menopausal before the age of 45?
(9) Ms. answer: Have you ever had no menstruation for more than 12 months in a row? (except during pregnancy)
(10) Men: Have you ever experienced impotence or lack of sexual desire?
As long as the answer to one of the questions is “yes”, it is positive.
2 Osteoporosis Self Assessment Tool for Asian (OSTA)
OSTA index = (weight – age) × 0.2
Risk level OSTA index
Low > -1
Medium -1 to -4
High < -4
(III) Risk prediction of osteoporosis
The WHO recommends the application of the Fracture Risk Prediction Easy Tool (FRAX) for calculating the risk of hip fracture and any significant osteoporotic fracture in subjects over the next 10 years.
The tool’s calculation includes femoral neck bone density and clinical risk factors. In the absence of femoral neck BMD is can be replaced by total hip BMD, however, in this calculation method, BMD at non-hip sites is not recommended. In the absence of bone densitometry, FRAX also provides a calculation method using only body mass index (BMI) and clinical risk factors for assessment.
The common risk factors for fracture identified in FRAX are: age; sex; low BMD; low body weight defined as ≤19 kg/m2; previous history of fragility fracture; treatment with glucocorticoids: any dose, oral for 3 months or longer; smoking; excessive alcohol consumption; combination of other diseases causing secondary osteoporosis
Not applicable to the population: clinically diagnosed osteoporosis, i.e. bone mineral density (T-value) below -2.5, or a fragility fracture has occurred, treatment should have been started promptly and FRAX assessment is not necessary.
Population:People who have not had a fracture and have low bone mass (T-value > 2.5), because of clinical difficulties in making treatment decisions, apply the FRAX tool to easily calculate the absolute risk of fracture in individuals and provide a basis for developing treatment strategies. The applicable population is men and women aged 40 to 90 years old, and individuals <40 and >90 years old are counted as 40 and 90 years old, respectively.
(IV) Falls and their risk factors
1. Environmental factors
Dark light; obstacle on the road; slippery road; loose carpet; lack of handrails in the bathroom
2. Health factors
Age; female; cardiac arrhythmia; poor vision; acute incontinence; history of previous falls; upright hypotension
Mobility disorders; medications (sleep medications, anticonvulsants, psychotropic drugs, etc.); sedentary; lack of exercise; depression; mental and cognitive disorders; anxiety and impulsivity; vitamin D deficiency [blood 25 hydroxyvitamin D <30ng/mL (75nmol/L)]; malnutrition
3 Neuromuscular factors
Poor balance; muscle weakness; hunchback; sensory retardation
4 Fear of falling
IV Diagnosis and differential diagnosis
The complete clinical diagnosis of osteoporosis should include two aspects: determination of osteoporosis and exclusion of other diseases affecting bone metabolism.
(A) Diagnosis of osteoporosis
The general criteria used clinically to diagnose osteoporosis are the occurrence of fragility fractures and/or low bone mineral density. There is a lack of clinical means to directly measure bone strength; therefore, bone mineral density and bone mineral content measurements are objective quantitative indicators for the clinical diagnosis of osteoporosis and for evaluating the extent of the disease.
1 Fragility fracture
This refers to fractures that occur without trauma or minor trauma, which are a clear manifestation of decreased bone strength and the end result and comorbidity of osteoporosis. The clinical diagnosis of osteoporosis is made when a fragility fracture occurs.
2 Diagnostic criteria (based on bone densitometry)
The occurrence of osteoporotic fractures is associated with a decrease in bone strength, which is determined by bone density and bone mass. BMD reflects about 70% of bone strength, and low BMD with other risk factors increases the risk of fracture. Because there is no ideal method for direct measurement or assessment of bone strength, BMD measurement is used clinically as the best quantitative standard for diagnosing osteoporosis, predicting the risk of osteoporotic fracture, monitoring the natural course of disease, and evaluating the efficacy of pharmacological interventions.
BMD is the amount of bone per unit volume (bulk density) or per unit area (area density), both of which are measured in vivo by noninvasive techniques.
There are more methods of BMD and bone measurement, and the role of different methods in the diagnosis of osteoporosis, monitoring of the efficacy, and assessment of fracture risk varies. Clinical applications include dual-energy X-ray absorptiometry (DXA), peripheral dual-energy X-ray absorptiometry (pDXA), and quantitative computed tomography (QCT). Among them, DXA measurement is currently recognized as the gold standard for the diagnosis of osteoporosis by the international academic community.
[Diagnostic criteria based on bone densitometry].
It is recommended to refer to the diagnostic criteria recommended by the World Health Organization (WHO). Based on DXA measurement: Bone density value less than 1 standard deviation below the peak bone mass of normal adults of the same sex and race is considered normal; a decrease of 1 to 2.5 standard deviations is considered low bone mass (reduced bone mass); a decrease equal to or greater than 2.5 standard deviations is considered osteoporosis. Severe osteoporosis is considered when the diagnostic criteria for osteoporosis are met and accompanied by one or more fractures.
Bone density is usually expressed as T-Score (T-value), T-value = (measured value – peak bone) / standard deviation of normal adult bone density.
Diagnosis
T-score:osteoporosis < -2.5
T-value is used for bone mineral density levels in postmenopausal women and men over 50 years of age. For children, premenopausal women and men under 50 years of age, BMD levels are recommended to be expressed as Z-values.
Z value = (measured value – mean value of BMD in the same age group)/standard deviation of BMD in the same age group
[Clinical indications for BMD measurement].
Bone densitometry is recommended if any of the following criteria are met.
-Female over 65 years of age and male over 70 years of age, with or without other risk factors for osteoporosis
-Females under 65 years of age and males under 70 years of age with one or more osteoporosis risk factors.
-Adults of both sexes with a history of fragility fracture or/and family history of fragility fracture
-Adults of both sexes with low levels of sex hormones from various causes
-Persons with pre-existing osteoporotic changes on radiographs
-People who are receiving osteoporosis treatment and are being monitored for efficacy
-History of diseases affecting bone metabolism or use of drugs affecting bone metabolism.
-Persons with positive answers to the IOF one-minute test questions
-OSTA results ≤ -1
(B) Differential diagnosis and laboratory tests for osteoporosis
1 Differential diagnosis of osteoporosis
Osteoporosis can be caused by a variety of etiologies. Before diagnosing primary osteoporosis, attention must be paid to exclude other diseases affecting bone metabolism to avoid underdiagnosis and misdiagnosis. Diseases that need to be differentiated include endocrine diseases affecting bone metabolism (gonadal, adrenal, parathyroid and thyroid diseases, etc.), immune diseases such as rheumatoid arthritis, intestinal and renal diseases affecting the absorption and regulation of calcium and vitamin D, malignant diseases such as multiple myeloma, long-term use of glucocorticoids or other drugs affecting bone metabolism, and various congenital and acquired abnormalities of bone metabolism.
2 Basic examination items
(1) Skeletal X-ray: focus on the relationship between any imaging changes in the bone and the disease
(2) Laboratory tests: blood and urine routine; liver and kidney function; calcium, phosphorus, alkaline phosphatase, serum protein electrophoresis, etc. Patients with primary osteoporosis usually have blood calcium, phosphorus, and alkaline phosphatase values in the normal range.
When there is a fracture, there is a mild increase in blood alkaline phosphatase value level. If abnormalities are found in the above tests, further investigations or referral to the relevant specialist is required for further differential diagnosis.
3. Discretionary tests: For further differential diagnosis, the following tests may be performed selectively, such as: blood sedimentation, gonadotropins, 25OHD, 1,25(OH)2D, parathyroid hormone, urinary calcium and phosphorus, thyroid function, cortisol, blood gas analysis, blood and urine light chain, tumor markers, and even radionuclide bone scan, bone marrow aspiration or bone biopsy.
4 Bone conversion biochemical markers
Biochemical markers of bone turnover are the metabolic (catabolic and synthetic) products of bone tissue itself, referred to as bone markers. They are divided into bone formation markers and bone resorption markers. The former represents bone metabolites during osteoblast activity and bone formation, while the latter represents metabolites during osteoclast activity and bone resorption, especially bone matrix degradation products. The measurement of these markers helps to determine the type of bone transformation, the rate of bone loss, the assessment of fracture risk, the understanding of disease progression, the selection of interventions, and the monitoring of treatment efficacy.
Markers of bone formation
–Serum alkaline phosphatase (ALP)
–Osteocalcin (OC)
–Bone derived alkaline phosphatase (BALP)
–Procollagen type I C-terminal prepeptide (PICP)
-Procollagen type I N-terminal prepeptide (CINP)
Markers of bone resorption
–Fast 2-hour urinary calcium/creatinine ratio
–Serum anti-tartrate acid phosphatase (TPACP)
–Collagen type I C-terminal peptide (S-CTX)
–urinary pyridinoline (Pyr)
–urinary deoxypyridinoline (D-Pyr)
–urinary type I collagen cross-linked C-terminal peptide (U-CTX)
–Urinary type I collagen cross-linked N-terminal peptide N-terminal peptide (U-NTX)
Among the above indicators, the International Osteoporosis Foundation (IOF) recommends type I procollagen N-terminal prepeptide (CINP) and serum type I collagen C-terminal peptide (S-CTX) as biochemical markers of bone turnover with relatively good sensitivity.
V Prevention and treatment
Once osteoporotic fractures occur, the quality of life decreases and various comorbidities occur, which can be disabling and fatal. Therefore, the prevention of osteoporosis is more realistic and important than the treatment.
(I) Basic measures
The foundation is important and indispensable, but it is not the “all” and “only”. The scope of “basic measures” includes.
–Primary and secondary prevention of osteoporosis
–Osteoporosis drug treatment and rehabilitation
The content of “basic measures” includes
1 Lifestyle modification
(1) A balanced diet rich in calcium, low in salt and moderate in protein
(2) Physical exercise and rehabilitation therapy with appropriate outdoor activities and sun exposure that contribute to bone health
(3) Avoid smoking and alcohol abuse, and be careful with drugs that affect bone metabolism.
(4) Take various measures to prevent falls and pay attention to the presence of diseases and drugs that increase falls.
(5) Strengthen protective measures for oneself and the environment (various joint protectors), etc.
2 Basic supplements for bone health
(1) Calcium: The recommended daily calcium intake for adults is 800mg (elemental calcium), which is a suitable dose to obtain the ideal bone peak and maintain bone health, and can be supplemented with calcium supplements if the calcium supply in the diet is insufficient; the recommended daily calcium intake for postmenopausal women and the elderly is 1000mg. Calcium intake can slow down the loss of bone and improve bone mineralization. When used for the treatment of osteoporosis, it should be combined with other drugs. There is insufficient evidence to suggest that calcium supplementation alone can replace other anti-osteoporosis drug therapy. Calcium selection should take into account its effectiveness and safety.
(2) Vitamin D: promotes calcium absorption, is beneficial for bone health, maintains muscle strength, improves physical stability, and reduces the risk of fracture.
Vitamin D deficiency can cause secondary hyperparathyroidism and increase bone resorption, which can cause and worsen osteoporosis. The recommended dose for adults is 200 IU/d; for the elderly, the recommended dose is 400-800 IU/d due to lack of sunlight and impaired intake and absorption. vitamin D should be used at a dose of 800-1200 IU/d for the treatment of osteoporosis and can also be used in combination with other drugs. The International Osteoporosis Foundation recommends that serum 25OHD levels in the elderly be equal to or higher than 30ng/mL (75nmol/L) to reduce the risk of falls and fractures.
(II) Pharmacological interventions
[Indications for pharmacological intervention].
Pharmacological treatment should be considered for those who have one of the following conditions.
(1) Those with confirmed osteoporosis (BMD: those with T≤-2.5), regardless of whether there has been a fracture or not.
(2) Patients with low bone mass (BMD: -2.5 < T ≤ -1.0) and more than one risk factor for osteoporosis, with or without previous fracture.
(3) In the absence of bone densitometry, pharmacological treatment should also be considered in those with one of the following conditions.
–have had a fragility fracture
–OSTA screening for high risk
–FRAX tool calculated the probability of hip fracture ≥ 3%, or the probability of any significant osteoporotic fracture ≥ 20% (temporarily borrowed from foreign treatment thresholds, which are not yet available for the Chinese.)
[Anti-osteoporosis drugs].
There are various anti-osteoporosis drugs with different mechanisms of action. They may mainly inhibit bone resorption; or promote bone formation, and there are also some drugs with multiple mechanisms of action. Clinical judgment of the efficacy of anti-osteoporosis drugs includes whether they can improve bone mass and bone quality, and ultimately reduce the risk of fracture. The standardized application of anti-osteoporosis drugs that have been approved for marketing in China is described as follows (in alphabetical order by drug name).
1 Bisphosphonates (Bisphosphonates)
Bisphosphonates are stable analogues of pyrophosphonates, which are characterized by the presence of P-C-P groups. Bisphosphonates bind with high affinity to skeletal hydroxyapatite and specifically bind to the surface of osteoclasts with active bone transformation to inhibit the function of osteoclasts, thus inhibiting bone resorption. The potency of different bisphosphonates to inhibit bone resorption varies widely, and therefore the dose and usage of different bisphosphonates in clinical practice varies.
2 Calcitonin
Calcitonin is a calcium-regulating hormone that inhibits the activity of osteoclasts and reduces the
Calcitonin is a calcium-regulating hormone that inhibits osteoclast activity and reduces the number of osteoclasts, thereby reducing bone loss and increasing bone mass. Another prominent feature of calcitonins is their ability to provide significant relief from bone pain. They are effective for chronic pain caused by osteoporotic fractures or skeletal deformities and bone pain caused by bone tumors and other diseases. It is more suitable for osteoporosis patients who have bone pain. Two preparations: salmon calcitonin and eel calcitonin analogue. Indications: SFDA approved indication for the treatment of postmenopausal osteoporosis.
Efficacy: Clinical studies have demonstrated increased bone density in the lumbar spine and hip in patients with osteoporosis, and 200 IU daily of synthetic salmon calcitonin nasal spray reduces the risk of vertebral and non-vertebral fractures; it significantly relieves bone pain.
Dosage: Salmon calcitonin nasal spray 200IU/day; injection 50IU/dose, subcutaneous or intramuscular, 2-7 times per week depending on the condition. Eel calcitonin 20IU/week, intramuscular injection.
Precautions: A few patients may have adverse reactions such as facial flushing, nausea, etc. Occasionally, allergic phenomena may be observed, and it can be determined whether to do allergy test according to the requirements of the drug instruction.
3 Estrogens
Estrogenic drugs can inhibit bone conversion and stop bone loss. They include estrogen (ET) and estrogen and progestin (EPT) supplementation therapy. Can reduce the risk of osteoporotic vertebral and non-vertebral fractures. An effective means of preventing and treating postmenopausal osteoporosis. Specifically included in national guidelines as a drug for the prevention and treatment of osteoporosis in menopausal women.
Indications: Perimenopausal and postmenopausal women before the age of 60, especially those with menopausal symptoms (e.g., hot flashes, sweating, etc.) and symptoms of genitourinary tract atrophy.
Contraindications: Estrogen-dependent tumors (breast cancer, endometrial cancer), thrombophilia, unexplained vaginal bleeding, active liver disease and connective tissue disease are absolute contraindications. Use with caution in cases of uterine fibroids, endometriosis, family history of breast cancer, gallbladder disease and pituitary prolactinoma.
Efficacy: Clinical studies have demonstrated an increase in bone mineral density in the lumbar spine and hip in patients with osteoporosis and a decrease in the risk of vertebral and non-vertebral fractures; significant relief of menopause-related symptoms.
It is recommended that hormone supplementation therapy follow the following principles.
(1) Clear indications and contraindications (to ensure that the benefits outweigh the harms)
(2) Start early in menopause (<60 years) for greater benefit and less risk
(3) Application of the lowest effective dose
(4) Individualization of treatment regimen
(5) Localized treatment of localized problems
(6) Adherence to regular follow-up and safety monitoring (especially breast and uterus)
(7) Whether to continue the drug should be evaluated annually according to the characteristics of each woman for pros and cons.
4 Parathyroid hormone (PTH)
PTH is the representative current drug for promoting bone formation: small doses of rhPTH (1-34) have a pro-bone formation effect.
Indications: It has been approved for the treatment of severe osteoporosis in men and women abroad and will be available soon in China.
Efficacy: Clinical trials have shown that rhPTH(1-34) is effective in treating postmenopausal osteoporosis improving bone density and reducing the risk of vertebral and non-vertebral fractures.
Usage: Injectable preparation, general dose 20ug/d,subcutaneous injection.
Precautions: It must be applied under the guidance of a professional physician. Blood calcium levels should be monitored during administration to prevent the occurrence of hypercalcemia. The duration of treatment should not exceed 2 years.
5 Selective estrogen receptor modulators (SERMs)
SERMs are not estrogens and are characterized by their selective action on estrogen target organs and different biological effects upon binding to different estrogen receptors. For example, SERMs raloxifene, which have been marketed both domestically and internationally, bind to estrogen receptors on bones, exhibit estrogen-like activity and inhibit bone resorption. In contrast, on the breast and uterus, it exhibits anti-estrogenic activity and thus does not stimulate the breast and uterus.
Indications: The indications that have been approved by SFDA in China are for the treatment of postmenopausal osteoporosis.
Efficacy: Clinical trials have shown that Raloxifene can reduce bone conversion to premenopausal levels in women, stop bone loss, increase bone density to reduce the risk of vertebral fractures, and reduce the incidence of estrogen receptor-positive invasive breast cancer.
Dosage: One tablet of raloxifene 60mg daily
Precautions: A small number of patients may experience hot flashes and lower extremity cramps while taking the drug. It is temporarily contraindicated in perimenopausal women with severe hot flashes.
6 Strontium salt
The chemical structure of strontium is similar to calcium and magnesium, and there are small amounts of strontium in normal human soft tissues, blood, bones and teeth. Synthetic strontium salt ranelate (Strontium Ranelate) is a new generation of anti-osteoporosis drugs.
7 Active vitamin D and its analogues
include 1,25 dihydroxyvitamin D3 (osteotriol) and 1αhydroxyvitamin D3 (α-osteotriol). The former is named active vitamin D because it no longer needs to be hydroxylated by liver and kidney hydroxylases to have an active effect, while 1α-hydroxyvitamin D3 needs to be hydroxylated by 25 hydroxylases to 1,25 bis-hydroxyvitamin D3 to have an active effect. Therefore, active vitamin D and its analogues are more suitable for the elderly, patients with renal insufficiency, and patients with 1α hydroxylase deficiency.
8 Vitamin K2 (tetraene-methylnaphthoquinone)
Animal tests and clinical trials have shown that it can promote bone formation and has some inhibitory effect on bone resorption.
9 Phytoestrogens
There is no strong clinical evidence that current phytoestrogen preparations have clear efficacy in improving bone density and reducing fracture risk.
10 Traditional Chinese Medicine
There is a lack of large clinical studies on Chinese medicine to improve bone density and reduce fracture risk, and further research is needed on long-term efficacy and safety.
Efficacy monitoring
Systematic observation of changes in bone mineral density in the mid-axis every 6-12 months will help evaluate the efficacy of the drug.
Note that methods such as peripheral dual-energy X-ray bone densitometry and quantitative bone ultrasound to evaluate peripheral bone density and bone quality do not reflect the response of the spine and hip to drug therapy and are therefore not suitable for monitoring the efficacy of the drug.