【Recommended collection】10 kinds of "anti-osteoporosis treatment drugs" inventory: standardize the benefits and risks of medication balance

On October 15, 2022, the online conference of the "13th Chongyang Endocrine and Metabolism Summit" hosted by the Endocrinology and Metabolism Branch of the Chinese Geriatric Society was successfully held
.
At the meeting, Professor Zhang Xingguang, director of the Department of Endocrinology of the Seventh Medical Center of the PLA General Hospital, brought a wonderful academic lecture on the topic of "Risks and Benefits in the Treatment of Osteoporosis in the Elderly", and systematically inventoried the benefits, risks, precautions and disposal methods of 10 anti-osteoporosis treatment drugs.

Current situation of osteoporosis epidemic in China

Professor Zhang Xingguang pointed out that China is the country with the largest absolute number of elderly people in the
world.
At present, the population over 60 years old has exceeded 210 million, the population over 65 years old is nearly 140 million, and the prevalence of osteoporosis in people over 50 years old in China is 14.
4% for men and 20.
7%
for women.

Osteoporotic fracture is a huge harm, is one of the main causes of disability and death in elderly patients, within 1 year after the occurrence of hip fracture, 20% of patients will die of various complications, about 50% of patients are disabled, the quality of life is significantly reduced
.

Overview: Classification of anti-osteoporosis drugs and treatment recommendations

1.
Indications for anti-osteoporosis drug treatment

➤ Those who develop vertebral fragility fractures (clinical or asymptomatic) or hip fragility fractures

➤DXA bone density (lumbar spine, femoral neck, total hip, or distal radius 1/3) T-value ≤-2.
5, regardless of whether there has been a fracture

➤ People with low bone mass (bone density -2.
5< T-value <-1.
0) have one of the following:

Have had fragility fractures in certain areas (upper humerus, distal forearm, or pelvis)

· The FRAX® tool calculates a hip fracture probability of ≥3% or any major osteoporotic fracture in the next 10 years ≥ 20%

2.
Drug classification and treatment recommendation

Anti-osteoporosis drugs mainly include bone resorption inhibitors, bone formation promoters, other mechanism drugs and traditional Chinese medicine
.

➤ Preferred: drugs with a wider spectrum of anti-fracture (such as alun sodium phosphate, zolenic acid, risseb phosphate sodium and denosumab).

➤ Patients at low or moderate risk of fracture (eg, young postmenopausal women, low bone density but no history of fracture): oral agents
are preferred.

➤ Injection preparations (such as zoleitonic acid, teriparatide, or denosumab
) may be considered for patients with intolerance, contraindications, poor compliance, and high fracture risk (such as patients with multiple vertebral fractures or extremely low bone density in elderly patients with hip fractures).

➤ Estrogen or selective estrogen receptor modulators (SERMs) may be considered for patients who are only at high risk of vertebral fracture and who are not at high risk of hip and nonvertebral
fractures.

➤Patients with new fractures and pain may consider short-term use of calcitonin
.

Table 1 Summary of anti-osteoporosis drugs

1.
Calcium

Multiple guidelines recommend calcium and vitamin D as the cornerstones
of through-osteoporosis therapy.
The recommended intake of calcium for adults is 800mg/d (elemental calcium), the recommended intake of calcium for people aged 50 and above is 1000-1200mg/d, and nutritional surveys show that Chinese residents consume about 400mg of elemental calcium daily, so it is still necessary to supplement elemental calcium about 500~600mg/d
.

➤ Benefits: Adequate calcium intake is beneficial
for achieving ideal bone peak, slowing bone loss, improving bone mineralization and maintaining bone health.

➤ Risks: gastrointestinal reactions, constipation, hypercalcemia, kidney stones
.

➤ Note: The selection of the agent should consider its calcium content, safety and efficacy
.
Very large doses of calcium supplementation may increase the risk of
kidney stones and cardiovascular disease.

➤Contraindications: Hypercalcemia
.

How to supplement calcium reasonably?

➤Calcium carbonate has high calcium content, high absorption rate, and is easily soluble in gastric acid
.

➤Calcium citrate has low calcium content, but good water solubility, small gastrointestinal adverse reactions, citric acid may reduce the occurrence of kidney stones, suitable for gastric acid deficiency and patients
with the risk of kidney stones.

➤ Do not overdose
on calcium supplementation.
Pay attention to diet conditioning, eat more fresh vegetables, fruits, cereals rich in plant fiber, etc.
, drink water reasonably to increase stool volume, you can exercise more, help promote intestinal defecation, relieve constipation
.

➤ Studies have found that calcium supplementation prevents the risk of kidney stones by reducing the availability of oxalic acid in the
intestine and its urinary excretion.
However, calcium supplementation, if taken between meals or before bedtime, may increase the risk of
kidney stone formation.

Table 2 Summary of calcium

Second, vitamin D

1.
Active vitamin D

Active vitamin D and its analogues mainly include 1a hydroxyvitamin D3 (a-calciferol) and 1,25 bishydroxyvitamin D3 (calcitriol), because it does not require kidney 1a hydroxylase hydroxylation to be active, so it is named active vitamin D and its analogues
.
Recommended for patients
older than 65 years or with serum creatinine clearance less than 60 ml/min and 1a hydroxylase deficiency or decrease.

➤ Benefits: Adequate vitamin D can increase intestinal calcium absorption, promote bone mineralization, maintain muscle strength, improve balance and reduce the risk of
falls.
Vitamin D insufficiency can lead to secondary hyperparathyroidism and increase bone resorption, which can cause or worsen osteoporosis
.
Vitamin D deficiency can also affect the efficacy
of other anti-osteoporotic drugs.

➤ Risk: hypercalcemia, kidney stones
.

➤ Notes:

1) Active vitamin D is recommended to monitor urinary calcium phosphorus and blood calcium phosphorus levels for 1 month, 3 months and 6 months of treatment, and then monitor blood calcium phosphorus, urinary calcium phosphorus and kidney function
twice a year.
Patients with chronic renal insufficiency who require continuous dialysis should monitor blood PTH, calcium, and phosphorus
.

2) The active vitamin D half-life is short, high urine calcium or high blood calcium, immediately reduce or stop the drug, reduce the intake of calcium and calcium-containing foods, and most of the blood calcium levels can recover
quickly.

3) Patients with kidney stones should be used
with caution.

2.
Regular vitamin D

The recommended intake of vitamin D for adults is 400 lU (10ug)/d; Elderly people aged 65 and above often have vitamin D deficiency due to lack of sunlight and intake and absorption disorders, and the recommended intake is 600lU (15ug)/d; When vitamin D is used for the prevention and treatment of osteoporosis, the dose can be 800~1200lU/d, and the maximum intake can be tolerated as 2000lU (50ug)/d
.

Blood 25(OH)D levels that cause vitamin D toxicity are often above 224 ng/ml (560 nmol/L), and the corresponding vitamin D supplement exceeds 30,000 lU
per day.
The risk of toxicity and hypercalcemia caused by physiological dose supplementation of ordinary vitamin D is very small, and generally does not increase the risk of
renal stones, renal calcium salting, and renal function damage.
Therefore, routine monitoring of blood and urine calcium
is not necessary.
Guidelines do not recommend the use of active vitamin D to correct vitamin D deficiency, and do not recommend a single high-dose regular vitamin D supplementation
for 1 year.

3.
Bisphosphonate

Bisphosphonates, a stable analogue of pyrophosphate, is currently the most widely used anti-osteoporosis drug
in clinical practice.
Ditenate has a high affinity for bone hydroxyapatite and can specifically bind to the bone surface where bone remodeling is active, inhibit osteoclast function, and thus inhibit bone resorption
.

➤ Benefits: Increases bone density in the lumbar spine and hip in patients with osteoporosis, and reduces the risk of
vertebral, non-vertebral and hip fractures.

➤ Risks:

1) Gastrointestinal adverse reactions: A small number of patients may have mild gastrointestinal reactions after oral administration of bisphosphonate, including epigastric pain, acid reflux and other symptoms
.
Patients with active gastric and duodenal ulcer, reflux esophagitis, and functional esophageal mobility disorders should be used
with caution.
If intestinal malabsorption is present, it may affect drug absorption
.

2) Transient "influenza-like" symptoms: the first oral or intravenous infusion occurs more, and there can be transient fever, bone pain and myalgia and other influenza-like adverse reactions, which are significantly relieved within 3 days of medication, and those with obvious symptoms can be treated symptomatically with non-steroidal anti-inflammatory drugs or other antipyretic analgesics
.

3) Renal toxicity: about 60% of bisphosphonates entering the blood are excreted from the kidneys in their original form, especially intravenous bisphosphonated drugs, renal function should be tested before each administration, and creatinine clearance < 35mL/min patients are banned<b10>.
As much as possible to hydrate the patient, the time of intravenous zoledronic acid should not be less than 15 minutes, and the intravenous infusion time of sodium Iban phosphate should not be less than 2 hours
.

4) Osteonecrosis of the mandible:

Rare
.

The vast majority (more than 90%) occur in patients with malignant tumors after high-dose bisphosphonate injections, and in patients with severe oral diseases, such as severe periodontal disease or multiple dental procedures
.

These drugs
are not recommended for patients with severe oral diseases or who require dental surgery.

Complete necessary oral surgery before starting anti-bone resorption therapy, use antibiotics before and after oral surgery, use antibacterial mouthwash, and properly close wounds after tooth extraction to maintain good oral hygiene
.

For high-risk patients (accompanied by diabetes, periodontal disease, glucocorticoids, immunodeficiency, smoking, etc.
) who need complex invasive oral surgery, it is recommended to suspend bisphosphonate treatment for 3~6 months, and then perform oral surgery for 3 months after surgery, if there is no special oral condition, the use of bisphosphonate
can be resumed.

5) Atypical femoral fracture (AFF): that is, fractures that occur below the trochanter of the femur to the femoral ankle under low violence, AFF may be related to
long-term use of bisphosphonates.
In patients with long-term bisphosphonate use (more than 3 years), if thigh or groin pain develops, double femoral x-rays should be performed to determine the presence of AFF, MRI, or nuclear bone scan
.
Pay attention to the drug holiday, as soon as AFFF occurs, the use of anti-bone resorption drugs
such as bisphosphonates should be stopped immediately.

Table 3 Summary of bisphosphonate drugs

Fourth, calcitonin

Calcitonin is a calcium-regulating hormone that can inhibit the biological activity of osteoclasts and reduce the number of osteoclasts; At present, there are two kinds of calcitonin preparations used in clinical practice: eel calcitonin analogue (calcitonin) and salmon calcitonin
.

➤ Benefits: Increases bone density in the lumbar spine and hip in patients with osteoporosis, and reduces the risk of
vertebral fractures.
Relieves bone pain and is effective
for osteoporosis and bone pain caused by fractures.

➤ Risk: The overall safety of calcitonin is good, and a small number of patients have adverse reactions such as facial flushing and nausea after use, and occasionally allergic phenomena
.
A 2012 European Medicines Agency's Committee on Human Drug Institutions found through meta-analysis that long-term use (6 months or more) with oral or nasal forms of calcitonin was associated with a slight increased risk of malignancy, and it was recommended that the continuous use of calcitonin generally not exceed 3 months
.

5.
Menopause hormone therapy drugs

Menopause hormone therapy includes estrogen replacement therapy (ET) and estrogen and progestin replacement therapy (EPT).

➤Benefits: Reduce bone loss, reduce the risk of osteoporotic vertebral, non-vertebral and hip fractures, and are effective measures
to prevent and treat postmenopausal osteoporosis.

➤ Risks: 1) Endometrial cancer; 2) breast cancer; 3) cardiovascular diseases; 4) thrombosis; 5) Increased body mass

1.
Several problems that need to be paid attention to in menopausal hormone therapy

➤Endometrial cancer: Women with uterus who supplement estrogen only for a long time may increase the risk of endometrial cancer, so women with uterus must be combined with progestogen
when using estrogen therapy.

➤ Breast cancer: The risk of breast cancer increased after 5 years in the estrogen plus pregnancy induction group, and the relationship between hormone therapy and breast cancer mainly depends on the progestogen and the length of
its application.

➤ Cardiovascular disease: Women without risk factors for cardiovascular disease, who start hormone therapy before the age of 60 or less than 10 years after menopause, may have a certain protective effect
on their cardiovascular disease.

➤ Thrombosis: menopausal hormone therapy mildly increases the risk of thrombosis, thrombosis is a contraindication to hormone therapy, and non-oral estrogen has a lower
risk of thrombosis because it does not have a first-pass effect on the liver.

➤ Increased body mass: The use of large doses of estrogen will cause water and sodium pig retention and body weight increase
.

2.
Principles of hormone supplementation therapy

1) Clarify the pros and cons of treatment

2) Early menopause start use (< 60 years old or within 10 years of menopause), the benefit is greater and the risk is smaller

3) Apply the lowest effective dose

4) Individualized treatment plan

5) Local treatment of local problems

6) Adhere 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

6.
Selective estrogen receptor modulators

Selective estrogen receptor modulators (SRMs) are not estrogens, but bind to estrogen receptors, causing different changes in receptor spatial conformation in different target tissues, thereby exerting different biological effects
similar to or antagonizing estrogen in different tissues.
Binds to estrogen receptors in the bones and exerts estrogen-like effects; In the breast and uterus, it plays an antagonistic
effect on estrogen.
Drug involved: raloxifene
.

➤ Benefits: Inhibit bone resorption, increase bone density, reduce the risk of vertebral fracture; For the prevention and treatment of
postmenopausal osteoporosis.
It does not stimulate the breast and uterus, and studies have shown that it reduces the incidence
of estrogen receptor-positive invasive breast cancer.
Raloxifene does not increase the risk of
coronary artery disease and stroke.

➤ Risk: A small number of patients will experience hot flashes and lower limb spasms during
medication.
Mildly increased risk of venous embolism has been reported abroad, but no similar reports have been seen
in China.

Seven.
Parathyroid hormone analogues

Parathyroid hormone analogue (PTHa) is a representative drug that promotes bone formation, and teriparatide that has been marketed in China is a recombinant human parathyroid hormone aminoterminal 1-34 active fragment (rhPTH1-34), which is characterized by effective treatment of severe osteoporosis
.
The complete indications of this product are: it is suitable for the treatment of osteoporosis in postmenopausal women with a high risk of fracture, which can significantly reduce the risk of vertebral and non-vertebral fractures in postmenopausal women, but the effect on reducing the risk of hip fractures has not been proven
.

PTH acts on bone, kidney and small intestine, increasing blood Ca2+ and regulating calcium and phosphorus metabolism
.
PTH mobilizes bone calcium to the blood (osteoclastic activity), so why is PTH an anti-osteoporotic?

Because low-dose PTH agonizes the osteoblast membrane PTH receptor, through the adenylate cyclase system, the effect of bone formation is greater than bone resorption; However, high-dose PTH activates the phosphoesterase C system through PTH receptors, enhances osteoclast function, and makes the bone resorption effect exceed the osteogenic effect
.

➤ Benefits: Intermittent use of low-dose PTHa can stimulate osteoblast activity, promote bone formation, increase bone density, improve bone mass, and reduce the risk
of vertebral and non-vertebral fractures.

➤ Risk: Hypercalcemia

➤ Note: A small number of patients have a transient mild increase in blood calcium concentration after injection of teriparatide and return to the baseline level
within 16 to 24 hours.
Blood calcium levels should be monitored during medication to prevent the occurrence of hypercalcemia; The duration of treatment is no more than 2 years
.

➤Contraindications: complicated by malformed osteitis, history of radiotherapy for bone diseases, tumor bone metastasis and hypercalcemia; Creatinine clearance less than 35ml/min; adolescents younger than 18 years of age and adolescents with unclosed epiphysis; Those
who are allergic to this product.

➤ Others: In the 7-year post-marketing osteosarcoma surveillance study in the United States, no causal relationship between teriparatide and human osteosarcoma was found; The treatment time of teriparatide should not exceed 24 months, and anti-bone resorption drugs should be used sequentially after discontinuation to maintain or increase bone density and continuously reduce the risk of
fracture.

VIII.
Strontium salt

Strontium is one of the essential trace elements of the human body, participating in a variety of physiological functions and biochemical effects
of the human body.
Strontium has a chemical structure similar to calcium and magnesium, and is present in small amounts in normal human soft tissues, blood, bones, and teeth
.
Involves the drug strontium ranelate but is currently in a restrictive drug
.

➤Benefits: In vitro experiments and clinical studies have confirmed that strontium ranelate can act on osteoblasts and osteoclasts at the same time, with the dual effects of inhibiting bone resorption and promoting bone formation, and can reduce the risk
of vertebral and non-vertebral fractures.

➤ Risk: nausea, diarrhea, headache, dermatitis and eczema, generally occurring at the beginning of treatment, mild degree, mostly temporary, tolerable
.
Drug eruptions with eosinophilia and rare systemic symptoms
.
Use
with caution at high risk of venous thrombosis.
Risk of
serious cardiovascular and cerebrovascular adverse reactions.

9.
Vitamin K

Menatetrenone, a homotype of vitamin K2, is a coenzyme of γ-carboxylase enzymes that play an important role
in the formation of γ-carboxyglutamate.

➤ Benefits: Promote bone formation, and have a certain inhibition of bone resorption, can mildly increase the bone mass
of osteoporosis.

➤ Risk: Less
.

➤ Note: The main adverse reactions include stomach upset, abdominal pain, skin itching, edema and mild elevation
of transaminases.

➤ Contraindications: patients taking warfarin (weakens the effect of warfarin).

10.
RANKL inhibitors

Denosumab is a nuclear factor kappa-B receptor activating factor ligand (RANKL) inhibitor, which is a fully humanized monoclonal antibody specific RANKL, which can inhibit the binding of RANKL to its receptor RANK, reduce osteoclast formation function and survival, and has good long-term tolerability and low incidence of adverse events
.

➤ Benefits: Increases lumbar spine and hip bone density in patients with osteoporosis, and reduces the risk of
vertebral, non-vertebral and hip fractures.
Few adverse reactions, good tolerability, significant curative effect, no renal metabolism, renal insufficiency does not need to adjust the dose
.

➤ Risk: hypocalcemia, severe infections (cystitis, upper tract infection, pneumonia, cutaneous cellulitis, etc.
), rash, itchy skin, muscle or bone pain, etc.
; Long-term use may excessively inhibit bone resorption, resulting in osteonecrosis of the jaw or atypical femoral fracture
.

➤ Note: Hypocalcemia must be corrected before treatment, and sufficient calcium and vitamin D should be supplemented before and after treatment;

➤ Contraindications: hypocalcemia
.

Indications for denosumab approved in China in June 2020: osteoporosis in postmenopausal
women at high risk of fracture.
In postmenopausal women, this product can significantly reduce the risk of
vertebral, non-vertebral and hip fractures.

Indications for denosumab in the EU and USA:

1) treatment of osteoporosis in postmenopausal women with high fracture risk;

2) treatment of osteoporosis in men at high risk of fracture to increase bone mass;

3) treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture;

4) men with non-metastatic prostate cancer at high risk of fracture receiving androgen deprivation therapy to increase bone mass;

5) Women with high fracture risk of breast cancer receiving aromatase inhibitor therapy to increase bone mass
.