Get urgent help for muscle spasms, twitching or cramps, or numbness or tingling around the mouth or in the fingers after denosumab, especially with advanced kidney disease (possible severe low calcium). Also seek help for chest pain, painful or difficult swallowing or new heartburn on an oral bisphosphonate, or for swelling of the face or throat or trouble breathing after any dose.
Key points
- Bisphosphonates (alendronate, risedronate, zoledronic acid) and denosumab slow bone breakdown and lower fracture risk in osteoporosis. Calcium and vitamin D support them but do not replace them.
- Oral bisphosphonates only work, and only stay safe for the oesophagus, if taken exactly as directed: on waking, with plain water only, at least 30 minutes before food, drinks or other medicines, and staying upright.
- Rare but serious effects of all these medicines include osteonecrosis of the jaw and atypical femur fractures. Report new thigh or groin pain.
- Do not stop denosumab without a plan. Bone loss rebounds and multiple vertebral fractures can occur, so switch to another antiresorptive medicine.
- Since January 2024, denosumab has carried an FDA boxed warning for severe, sometimes fatal, low calcium in advanced chronic kidney disease (eGFR below 30), including dialysis.
How they work and who uses them
Bisphosphonates bind to bone and inhibit the cells that break it down. Denosumab is an antibody against RANK ligand, which osteoclasts need to form and work. US labels cover postmenopausal osteoporosis, osteoporosis in men and glucocorticoid-induced osteoporosis. Denosumab is also labelled to increase bone mass in men on androgen deprivation therapy for prostate cancer and in women on aromatase inhibitors for breast cancer. Oncology products use the same active ingredients at different doses (Zometa for zoledronic acid, Xgeva for denosumab). A person must not receive two products with the same active ingredient. Several denosumab biosimilars have been approved in the US since 2024.
How to take them
Oral alendronate and immediate-release risedronate
- Typical treatment doses: alendronate 70 mg once a week (or 10 mg daily); risedronate 35 mg once a week, 5 mg daily, 75 mg on two consecutive days a month, or 150 mg once a month.
- Take on rising, with a full glass (180 to 240 mL) of plain water. Do not use mineral water, coffee, juice or milk.
- Wait at least 30 minutes before the first food, drink or other medicine of the day. Waiting less time, or taking it with food, reduces absorption.
- Do not lie down for at least 30 minutes, and for alendronate not until after the first food. Never take it at bedtime.
- Take calcium, antacids and other medicines containing calcium, iron or magnesium at a different time of day, because they block absorption.
- Missed weekly alendronate: take it the morning after you remember, then return to your usual day. Never take two doses on the same day.
Delayed-release risedronate (Atelvia) is the exception: take it immediately after breakfast with at least 120 mL of water, because taking it fasting raises the risk of abdominal pain. Still stay upright for 30 minutes.
Zoledronic acid
For osteoporosis, give 5 mg by intravenous infusion over at least 15 minutes once a year (once every 2 years for prevention). Make sure the person is well hydrated first. Paracetamol (acetaminophen) after the infusion may reduce the flu-like acute-phase reaction. In trials this caused fever in 18%, muscle pain in 9% and joint pain in 7%, mostly within 3 days.
Denosumab
Denosumab 60 mg is given by subcutaneous injection every 6 months by a healthcare professional. If a dose is missed, give it as soon as possible and schedule the next one 6 months later. The label instructs patients to take calcium 1,000 mg and at least 400 IU of vitamin D daily.
Serious adverse effects
Oesophagus and stomach (oral bisphosphonates)
These can cause oesophagitis, oesophageal ulcers and erosions. Use caution with active upper GI problems such as Barrett's oesophagus, swallowing difficulty, gastritis or ulcers, and with aspirin or NSAIDs. Stop and seek review if swallowing becomes painful or difficult, or if chest pain or heartburn starts or worsens.
Osteonecrosis of the jaw
Exposed, non-healing jawbone, usually after tooth extraction or local infection. Risk factors include invasive dental work, cancer, chemotherapy, corticosteroids, angiogenesis inhibitors, poor oral hygiene, gum disease and poorly fitting dentures. Risk may rise with longer bisphosphonate use. The labels advise an oral examination before starting, and preventive dental care for people with risk factors. Maintain good oral hygiene, and tell the dentist about the medicine.
Atypical femur fractures
Low-trauma transverse or short oblique fractures of the thigh-bone shaft, sometimes on both sides. Anyone with new thigh, hip or groin pain needs imaging to rule out an incomplete fracture, and the other leg should be checked. Interrupting treatment should be considered.
Other
- Severe bone, joint or muscle pain, sometimes incapacitating, can occur with bisphosphonates. Stop if severe; most people improve after stopping.
- Denosumab: serious infections including cellulitis, skin reactions (dermatitis, eczema, rash) and allergic reactions including anaphylaxis.
- Zoledronic acid: acute kidney failure, rarely needing dialysis or fatal, even after a single dose.
Stopping, switching and drug holidays
- Bisphosphonates: the labels state that the best duration is not known. Reassess the need regularly. Consider stopping after 3 to 5 years in people at low fracture risk, and recheck their fracture risk periodically after stopping.
- Denosumab: after stopping, bone turnover rises above pretreatment levels by 9 months, and bone density returns to baseline within 18 months. New vertebral fractures occurred as early as 7 months (on average 19 months) after the last dose. A previous vertebral fracture predicted multiple fractures. Move to another antiresorptive medicine if denosumab is stopped, and plan this before starting.
Calcium and vitamin D
These amounts come from the US National Academies intake values as presented by MedlinePlus. Other countries publish slightly different figures.
- Calcium (RDA): 1,000 mg a day for adults 19 to 50 and men 51 to 70; 1,200 mg a day for women over 50 and everyone over 70. Food, especially dairy, is the preferred source. Add a supplement only to make up a shortfall.
- Calcium upper limit: 2,500 mg a day at 19 to 50 and 2,000 mg a day over 50, counting food and supplements. Long-term high intake raises kidney stone risk in some people.
- Supplements: absorption is best at no more than 500 mg at a time. Calcium carbonate is absorbed better with food. Calcium citrate is absorbed well with or without food.
- Vitamin D (RDA): 600 IU (15 micrograms) a day at 19 to 70, and 800 IU (20 micrograms) over 70. The upper limit for adults is 4,000 IU (100 micrograms) a day. Too much raises blood calcium and can damage the kidneys.
- Before treatment: correct low calcium before starting any of these medicines; it is a contraindication to all of them. For zoledronic acid, other disturbances of mineral metabolism (for example after thyroid or parathyroid surgery, or with malabsorption) must also be treated first. People over 70, those in care homes, those who are chronically ill and those with malabsorption may need vitamin D supplements or a 25-hydroxyvitamin D level.
Safety: what to check
- Contraindications: oral bisphosphonates should not be used with oesophageal strictures or achalasia, inability to stay upright for 30 minutes, or low calcium. Zoledronic acid is contraindicated with creatinine clearance below 35 mL/min or acute kidney injury. Denosumab is contraindicated in low calcium and in pregnancy.
- Kidneys: alendronate is not recommended below creatinine clearance 35 mL/min, and risedronate not below 30 mL/min. Before every zoledronic acid dose, check serum creatinine and calculate creatinine clearance (Cockcroft-Gault, actual body weight). Take extra care with older people, diuretics, dehydration and other nephrotoxic medicines.
- Denosumab in advanced CKD: no dose change is needed for kidney function, but with eGFR below 30 mL/min/1.73 m² or on dialysis the risk of severe hypocalcaemia is much higher. Before starting, assess CKD-mineral and bone disorder (intact PTH, calcium, 25(OH) and 1,25(OH)₂ vitamin D). Treatment should be supervised by an expert. Monitor calcium weekly for the first month after each dose and then monthly. Calcimimetics add to the risk.
- Dental: do an oral examination before starting, arrange a dental check and preventive dentistry for people with jaw-necrosis risk factors, and maintain oral hygiene during treatment.
- Pregnancy and breastfeeding: stop oral bisphosphonates if pregnancy occurs. Rule out pregnancy before denosumab and use effective contraception during treatment and for at least 5 months after the last dose. There is no information on denosumab in human milk.
- Older adults: watch hydration and kidney function before zoledronic acid, swallowing ability and posture with oral tablets, and calcium intake.
Frequently asked questions
Can I take my bisphosphonate with coffee or my other morning tablets?
No. Use plain water only and wait at least 30 minutes before coffee, food or other medicines. Take calcium supplements later in the day.
Do I need to stop my bisphosphonate before dental work?
Tell your dentist. For invasive procedures, the label notes that stopping a bisphosphonate may reduce jaw risk, but the decision is individual and made with your prescriber.
Can I just stop denosumab injections?
Not without a plan. Stopping causes rapid bone loss and can trigger several spinal fractures. Your prescriber should arrange another bone medicine.
Is more calcium better?
No. Aim for the recommended amount, mostly from food. Going above the upper limit adds risk, such as kidney stones, without extra benefit.
Sources
- US FDA-approved labeling, alendronate (Fosamax). DailyMed
- US FDA-approved labeling, risedronate (Actonel). DailyMed
- US FDA-approved labeling, risedronate delayed-release (Atelvia). DailyMed
- US FDA-approved labeling, zoledronic acid 5 mg (Reclast). DailyMed
- US FDA-approved labeling, denosumab 60 mg (Prolia). DailyMed
- US FDA Drug Safety Communication: boxed warning for severe hypocalcaemia with Prolia in advanced CKD, January 2024. fda.gov
- MedlinePlus. Calcium in diet. medlineplus.gov
- MedlinePlus. Vitamin D. medlineplus.gov
This article is for education and does not replace advice from a doctor or pharmacist who knows the person's history and other medicines.
