Medications for Treating Osteoporosis

General Recommendations:

• Supplement with vitamin D and calcium, unless advised otherwise by your doctor.
• Have your teeth checked before starting therapy (especially important for intravenous medications).
• Drink plenty of fluids, stay physically active, and maintain a healthy diet to support treatment.
• If you’re unsure about anything, always consult your doctor.

 Bone Remodeling and Bisphosphonates

Our bones are constantly undergoing remodeling – a process of breaking down (by osteoclasts) and rebuilding (by osteoblasts).
If bone breakdown dominates, bone loss increases.

Bisphosphonates are medications that inhibit bone breakdown and are mainly used to treat:

• Osteoporosis
• Paget’s disease
• Bone metastases in cancer
• Hypercalcemia (high calcium levels in the blood)

 Mechanism of Action:

Bisphosphonates are chemically similar to pyrophosphate, a natural bone component, but are more stable.
They bind to hydroxyapatite crystals in bones, especially where bone turnover is high.

There are two types:

1. Non-nitrogen-containing bisphosphonates (e.g., Etidronate, Clodronate):

• Absorbed by osteoclasts
• Disrupt energy production → osteoclasts die → less bone is broken down

2. Nitrogen-containing bisphosphonates (e.g., Alendronate, Risedronate, Zoledronate):

• Inhibit Farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway
• Prevent “prenylation” of proteins needed by osteoclasts → osteoclasts become inactive or die

 Effects:

• Reduces bone resorption
• Maintains or increases bone density
• Lowers the risk of fractures, especially in osteoporosis

Side Effects (selected):

• Gastrointestinal issues (especially with oral use)
• Jaw osteonecrosis (rare but serious, especially in high doses used for cancer)
• Atypical femur fractures (with long-term use)
• Flu-like symptoms after intravenous administration

Older bisphosphonates like Etidronate and Clodronate are no longer standard for osteoporosis due to lower effectiveness.
Ibandronate (Bondronate®) is still used in cancer-related bone disease and hypercalcemia.

 Preferred Drugs for:

• Postmenopausal osteoporosis
• Osteoporosis in men
• Glucocorticoid-induced osteoporosis

Commonly used:

• Alendronate
• Risedronate
• Ibandronate
• Zoledronate

These are well-researched, more effective, and have a better safety profile.

 Dosage & Application Overview

1. Alendronate

• Dose: 70 mg orally, once weekly
• Instructions: Take on an empty stomach with a full glass of water. Stay upright for 30 min.
  Do not use in bedridden patients due to risk of esophageal damage.

2. Risedronate

• Dose:
  • 35 mg orally, once weekly
  • or 150 mg orally, once monthly
• Instructions: Same as Alendronate

3. Ibandronate

• Dose:
  • 150 mg orally, once monthly
  • or 3 mg IV every 3 months
• Instructions (oral): Take on empty stomach, remain upright for 60 minutes

4. Zoledronate (Zoledronic Acid)

• Dose: 5 mg IV, once per year
• Application: IV infusion over at least 15 minutes
• Notes:
  • Ensure proper hydration before administration
  • Flu-like symptoms may occur after the first dose

General Tips for Oral Bisphosphonates:

• Only use plain water (not mineral water or other drinks)
• Avoid with food, milk, or other medications (absorption is reduced)
• If you have trouble swallowing or esophageal issues → prefer IV formulations

 Example: Choosing the Right Bisphosphonate

 Additional Notes:

• Calcium + Vitamin D supplementation is essential (unless there’s a hypercalcemia risk)
• Zoledronate is often preferred in women at high fracture risk
• Dental check-up before IV bisphosphonates is important due to risk of jaw osteonecrosis

Effectiveness Comparison: Alendronate vs Risedronate

 Conclusion: Both are equally effective for preventing spine and hip fractures.

 Tolerability & Practical Use

 Summary:

• Effectiveness: Comparable
• Risedronate: Possibly better for the stomach
• Choice depends on tolerability, patient preferences, and cost – not a major difference in effect

 Mechanism of Action of Denosumab:

1. RANKL is a signaling protein produced by osteoblasts and osteocytes.
2. It binds to the RANK receptor on precursor cells of osteoclasts.
3. This binding activates the maturation of osteoclasts, which then break down bone.

 Denosumab blocks RANKL → no activation of osteoclasts → bone breakdown is stopped or significantly reduced.

 Application:

• Dose: 60 mg subcutaneously every 6 months
• Brand name: e.g., Prolia®
• Indications:
  • Postmenopausal osteoporosis
  • Osteoporosis in men
  • Bone loss due to hormone-blocking therapies (e.g., for breast or prostate cancer)
  • High fracture risk or intolerance to bisphosphonates

 Advantages of Denosumab:

• Very effective in preventing fractures (spine, hip, and other bones)
• Easy to use – only twice a year
• No gastrointestinal side effects (no pills to swallow)
• Can be used in patients with impaired kidney function (with caution)

 Important Side Effects / Risks:

• Rebound effect after stopping:
  • Sudden bone loss and increased fracture risk (especially spine)
  • Must be followed by another osteoporosis treatment (e.g., bisphosphonate)
• Low calcium levels (hypocalcemia):
  • Especially in patients with kidney problems → supplement with calcium and vitamin D
• Jaw osteonecrosis:
  • Rare, mostly in cancer patients or at high doses
• Slightly increased risk of infections:
  • Because RANKL also plays a role in immune cells

 Conclusion:

Denosumab is a targeted and highly effective medication for osteoporosis.
It is especially useful for patients with:

• High fracture risk
• Bisphosphonate intolerance
• Reduced kidney function

 However, it requires long-term planning, as stopping it abruptly can be harmful.

 Romosozumab – Targeted Therapy for Osteoporosis

Romosozumab is a relatively new, targeted medication used to treat postmenopausal osteoporosis in women at high risk of fractures. It belongs to the group of anabolic bone agents, meaning it primarily builds bone and secondarily reduces bone breakdown.

 Mechanism of Action:

Romosozumab is a monoclonal antibody that specifically blocks the protein sclerostin.

 What is sclerostin?

• Produced by osteocytes (mature bone cells)
• Inhibits the activity and formation of osteoblasts (cells that build bone)
• Promotes bone resorption indirectly by supporting osteoclast function

Romosozumab blocks sclerostin:

•  Activates osteoblasts → more bone formation
•  Inhibits osteoclasts → less bone breakdown

 This makes Romosozumab unique among osteoporosis drugs: it actively builds bone and prevents bone loss at the same time.

 Use and Dosage:

• Brand name: Evenity®
• Administration: Subcutaneous injection (under the skin)
• Dosage:
  • 210 mg once per month
  • Given as two injections of 105 mg (usually in both upper arms)
• Treatment duration:
  • Maximum 12 months
  • Should be followed by antiresorptive therapy (e.g. bisphosphonates or Denosumab) to maintain the gained bone mass

 Effects:

• Significant increase in bone mineral density (BMD)
• Strong reduction of spinal and non-spinal fractures
• Fast onset of action, especially in the first month

 Important Warnings & Side Effects:

 Not recommended for patients with a recent heart attack or stroke within the past 12 months.

 When Is Romosozumab a Good Choice?

• Women with severe postmenopausal osteoporosis (e.g., multiple fractures)
• When rapid bone building is needed
• When other therapies have failed or are not tolerated

 Romosozumab in Men – Efficacy and Approval

 Efficacy in Men

BRIDGE Study (Phase III, placebo-controlled):

• 12 months of Romosozumab (210 mg/month) in men aged 55–90 with osteoporosis
• Results after 12 months:
  • +12.1% lumbar spine BMD vs +1.2% with placebo
  • +2.5% hip BMD vs –0.5% with placebo
  • Well tolerated, similar side effects, slightly more cardiovascular events (4.9% vs. 2.5%)

Retrospective study (Japan):

• 12 months in Japanese men
• Romosozumab: +13% spine BMD
• Denosumab: +4.5%
• Similar hip BMD gain

Small study (China):

• Elderly men with hip fractures
• Romosozumab led to higher BMD, better healing, and less pain compared to Alendronate

 Approval Status in Men

 Summary:

 Conclusion:

Romosozumab shows convincing effectiveness in men with osteoporosis.
However, official approval is still lacking in key regions like the EU and USA – in these areas, doctors may use it off-label.
In countries like Japan, it is already approved for men.

 Mechanism of Action of Tibolone:

Tibolone itself is a prodrug (an inactive precursor) that is converted in the body into three active metabolites. These have tissue-specific effects:

 Dosage and Administration:

• Standard dose:
  • 2.5 mg Tibolone orally once daily
• Use:
  • Long-term treatment is possible, usually after individual benefit-risk evaluation
• When to start:
  • No earlier than 12 months after the last menstrual period, as earlier use may cause spotting or bleeding

 Indications:

• Treatment of menopausal symptoms (e.g., hot flashes, mood swings, low libido)
• Prevention of postmenopausal osteoporosis, when other options are unsuitable
• Alternative to conventional hormone replacement therapy (HRT) – especially when breast tenderness, mood changes, or libido loss are prominent concerns

Contraindications / Risks:

Do not use Tibolone if you have or have had:

• Breast cancer (current or past)
• Endometrial cancer
• Thrombosis or embolism, or a history of these
• Liver disease
• Pregnancy or breastfeeding

 Possible Side Effects:

• Vaginal bleeding (especially at the beginning of therapy)
• Headaches
• Breast pain (rare)
• Acne, weight gain (due to androgenic effects)

 Conclusion:

Tibolone is a special type of hormone replacement therapy (HRT) that combines estrogenic, progestogenic, and androgenic effects, depending on the tissue.

It is a suitable option for postmenopausal women experiencing menopausal symptoms and at risk for osteoporosis – particularly if low libido is a concern.

However, like all forms of HRT, it is not without risks and should only be used after an individual assessment by a healthcare professional.

 Mechanism of Action – Teriparatide

Teriparatide is a medication used to treat osteoporosis. It belongs to the group of parathyroid hormone (PTH) analogs. Unlike most osteoporosis drugs that slow down bone breakdown, Teriparatide works by building new bone.

 How it works:

• Teriparatide is a synthetic fragment of human parathyroid hormone (PTH 1–34).
• In the body, natural PTH regulates calcium levels.
• Continuous high levels of PTH lead to bone loss. However:

 When Teriparatide is injected once daily, it has a bone-building effect:

• It activates osteoblasts (bone-forming cells).
• Bone formation outweighs bone resorption.
• Bone density increases, and the risk of fractures is reduced.
•  

 Administration

• Dosage: 20 μg subcutaneous injection, once daily
• Treatment duration: Maximum of 24 months
• Brand name: e.g., Forsteo®

 Benefits

• The only approved medication that directly stimulates bone formation
• Particularly useful for:
  • Severe osteoporosis
  • Multiple fractures
  • Failure of other osteoporosis treatments
  • Intolerance to bisphosphonates

 Side Effects

• Nausea, dizziness, headache
• Mild increase in blood calcium levels (hypercalcemia)
• Very rare: bone cancer (seen in animal studies with long-term high doses → why treatment is limited to 2 years)

 Summary

Teriparatide promotes bone formation by stimulating osteoblasts.
It is highly effective in severe osteoporosis but should be used only short-term.
After stopping treatment, a follow-up therapy with an antiresorptive drug (like bisphosphonates or Denosumab) is usually recommended to maintain the newly gained bone mass.

 Most Common Side Effects of Osteoporosis Medications

The most frequent side effect depends strongly on the type of medication.
Here is an overview by drug class:

1. Bisphosphonates (e.g., Alendronate, Risedronate, Ibandronate, Zoledronate)

• Oral (tablets):
  • Irritation of the esophagus / gastrointestinal discomfort
    • Common: heartburn, nausea, stomach pain
    • Especially if taken incorrectly (e.g., not staying upright, too little water)
• Intravenous (e.g., Zoledronate):
  • Acute phase reaction (“flu-like symptoms”)
    • Common: fever, muscle aches, headache, fatigue
    • Usually occurs 1–3 days after the infusion and lasts a few days

2. Denosumab (Prolia®)

• Most common side effects:
  • Muscle pain, joint pain, back pain
  • Urinary tract infections
  • Skin rashes
• Less common, but important:
  • Hypocalcemia (especially in patients with kidney disease)
  • Jaw osteonecrosis (rare – see next section)
  • Rebound effect after discontinuation → increased fracture risk

3. Raloxifene (SERM)

• Most common side effects:
  • Hot flashes
  • Leg cramps
  • Increased risk of thrombosis (deep vein thrombosis, pulmonary embolism – rare but relevant)

4. Teriparatide / Abaloparatide (Parathyroid hormone analogs)

• Common side effects:
  • Nausea
  • Dizziness
  • Headaches
  • Mild hypercalcemia

5. Romosozumab (Evenity®)

• Most common side effects:
  • Joint pain
  • Injection site reactions
• Important but rare:
  • Possible increased cardiovascular risk (e.g., stroke, heart attack)
    → Not approved for patients with recent cardiovascular events

 Summary of Common Side Effects by Drug Class

Risk of Jaw Osteonecrosis (MRONJ)

Medication-related osteonecrosis of the jaw (MRONJ) risk varies by drug class:

 1. Bisphosphonates (e.g., Alendronate, Ibandronate, Risedronate, Zoledronate)

• Oral bisphosphonates:
  • Very low risk in osteoporosis treatment (~1–10 cases per 100,000 patient-years)
• Intravenous bisphosphonates:
  • Slightly higher risk, but still low in osteoporosis (~10–50 cases per 100,000 patient-years)

Important:
In cancer patients receiving high-dose IV bisphosphonates, the risk is much higher (1–10%).

2. Denosumab (Prolia®)

• Risk: Comparable to IV bisphosphonates (~10–50 cases per 100,000 patient-years)
• Also higher in cancer treatment (as with bisphosphonates)

3. Selective Estrogen Receptor Modulators (SERMs) (e.g., Raloxifene)

• No known risk of jaw osteonecrosis

4. Teriparatide (PTH analog)

• No known risk
• May even be used to treat MRONJ in some cases

5. Romosozumab (Sclerostin antibody)

• No clear evidence of increased MRONJ risk in osteoporosis treatment

 Additional Risk Factors (besides medication):

• Tooth extractions or jaw surgery
• Poor oral hygiene / gum disease
• Smoking
• Treatment duration >3 years
• Use of corticosteroids or chemotherapy

 Conclusion:

 Because the risk of osteoporotic fractures is much higher than the risk of MRONJ, guidelines recommend starting treatment immediately when indicated.
A dental check-up can still be done after treatment begins.