Table 1.

Protocol and precautions of bone-modifying drugs (initiation time, treatment duration, precautions).

Drug name	Denosumab	Zoledronic acid	Ibandronate sodium	Incadronate disodium
Recommended initial dose and protocol	120 mg, SC on the upper arm, upper thigh, or abdomen, repeat every 4 weeks	4 mg, IV > 15 min, repeat every 3–4 weeks	6 mg, IV > 15 min, repeat every 3–4 weeks; loading therapy: 6 mg/day, IV > 15 min for 3 consecutive days, thereafter repeat every 3–4 weeks (6 mg, IV > 15 min once)	For most patients, ≤10 mg once; for patients > 65 years, 5 mg once (recommended); IV drip for 2–4 h every 3–4 weeks after dissolving in 500–1000 ml normal saline
Instructions	Bone-modifying drugs are recommended for patients with radiographic bone destruction or metastasis if there are no contraindications, but they are not recommended for patients with a risk of bone metastasis alone but undiagnosed. Therefore, relevant examinations before the drug application should include the above imaging examinations and serum markers, such as SPECT, PET-CT, MRI, ALP, and NTX.
Treatment duration	Bone-modifying drugs are recommended for patients with a life expectancy of at least 3 months, and the treatment duration is recommended at 18 to 24 months depending on the patients' tolerance and benefit. The total treatment duration may be prolonged by extending the treatment interval according to clinical judgment.
Precautions	1.When using bone-modifying drugs, the risk of SREs should be closely monitored, especially for patients with risk factors; if SREs occur during the treatment, bone-modifying drugs are still recommended to continue if they could reduce the risk of SREs recurrence. 2.Calcium (500 mg/day) and vitamin D (400 IU/day) are recommended when using bone-modifying drugs. 3.Considering the possible ADRs related to bone-modifying drugs, the pre-existing hypocalcemia should be corrected before the administration of bone-modifying drugs. It is recommended to perform an appropriate oral examination cooperating with the stomatology department in advance and pay attention to various factors (e.g. serum calcium, serum creatinine, phosphate, magnesium, renal function, etc.) to avoid invasive operations; during administration, it is suggested to closely monitor patients' health and adjust the treatment regimens according to the patients' conditions to maximize the medication safety.

Abbreviations: ADR, adverse reactions; ALP, alkaline phosphatase; MRI, magnetic resonance imaging; NTX, N-terminal telopeptide of type 1 collagen; SC, subcutaneous injection; SPECT, single-photon emission computed tomography; SRE, skeletal-related events; PET-CT, positron emission computed tomography; IV, intravenous injection; IV drip, intravenous drip.