Osteoporosis is a bone disease that causes a loss of bone density and strength, leading to an increased risk of fractures. Osteoporosis affects over 200 million people worldwide and causes over 8.9 million fractures annually. Identifying the most effective treatments for osteoporosis is critical for reducing fracture risk and the associated morbidity and mortality.
What is osteoporosis?
Osteoporosis is characterized by low bone mass and deterioration of the microarchitecture of bone tissue. This leads to increased bone fragility and susceptibility to fracture. Osteoporosis most commonly affects the hip, spine, and wrist. Major risk factors for osteoporosis include:
- Older age
- Female gender
- Family history of osteoporosis
- Low body weight or low BMI
- Nutritional deficiencies
- Smoking
- Excessive alcohol intake
- Physical inactivity
Osteoporosis develops when bone resorption outpaces bone formation. This leads to a decrease in bone mineral density (BMD). Osteoporosis is diagnosed based on measurement of BMD, most commonly by dual-energy x-ray absorptiometry (DXA). The World Health Organization defines osteoporosis as a BMD that lies 2.5 standard deviations or more below the average BMD of a young adult.
What are the consequences of osteoporosis?
The major consequence of osteoporosis is an increased susceptibility to fractures, also called osteoporotic or fragility fractures. The most common sites for osteoporotic fractures are the hip, spine, and wrist. However, fractures can occur at many sites, including the arm, rib, pelvis, and other bones.
Hip fractures are especially serious, with 20% of older adults dying within one year of a hip fracture. Hip fractures also lead to permanent disability in many cases. Vertebral fractures can cause back pain, deformity, and disability.
Osteoporotic fractures can lead to chronic pain, reduced mobility, disability, lost independence, and reduced quality of life. After an initial fracture, the risk of subsequent fractures is substantially increased.
What are the treatment options for osteoporosis?
There are several treatment options available for osteoporosis, which can be divided into medications and lifestyle approaches:
Medications
- Bisphosphonates – Alendronate, risedronate, ibandronate, and zoledronic acid. These medications slow bone resorption and increase BMD.
- Denosumab – A monoclonal antibody that inhibits bone resorption.
- Raloxifene – A selective estrogen receptor modulator (SERM) that maintains bone mass.
- Teriparatide – A parathyroid hormone analog that stimulates bone formation.
- Abaloparatide – A parathyroid hormone-related peptide analog that increases bone formation.
- Romosozumab – A sclerostin inhibitor that increases bone formation.
- Estrogen – Hormone therapy that reduces bone resorption.
Lifestyle Approaches
- Adequate calcium and vitamin D intake
- Weight-bearing and muscle-strengthening exercise
- Fall prevention strategies
- Avoidance of smoking and excess alcohol
- Maintenance of adequate nutrition and healthy body weight
What are the benefits and risks of osteoporosis medications?
Bisphosphonates
Benefits: Potent antiresorptive effects leading to increased BMD and reduced fracture risk. Oral bisphosphonates (alendronate, risedronate) reduce vertebral fractures by 40-50% and hip fractures by 40-60%. IV bisphosphonates (zoledronic acid) reduce vertebral fractures by 70% and hip fractures by 40%.
Potential risks: Upper gastrointestinal side effects, increased risk of atypical femur fractures and osteonecrosis of the jaw.
Denosumab
Benefits: More potent than bisphosphonates at increasing BMD and preventing fractures. Reduces vertebral fractures by 68%, hip fractures by 40%, and nonvertebral fractures by 20%.
Potential risks: Increased risk of serious infections, low calcium levels, osteonecrosis of the jaw.
Raloxifene
Benefits: Reduces vertebral fractures by 30-50%. Also may reduce risk of breast cancer.
Potential risks: Increased risk of blood clots, hot flashes, leg cramps.
Teriparatide
Benefits: Most effective for increasing BMD and reducing vertebral and nonvertebral fractures. Reduces vertebral fractures by 65% and nonvertebral fractures by 53%.
Potential risks: Limited to 2 years duration, increased risk of osteosarcoma in rats with lifetime use.
Abaloparatide
Benefits: Reduces major osteoporotic fractures by 86% and vertebral fractures by 43%. Increased BMD.
Potential risks: Limited data on long-term safety. Risk of osteosarcoma in rats with lifetime use.
Romosozumab
Benefits: Potently increases BMD and reduces fracture risk. Reduces vertebral fracture by 73%, nonvertebral fracture by 36%, and hip fracture by 38%.
Potential risks: Limited long-term safety data. Theoretical risk of osteosarcoma.
Estrogen
Benefits: Reduces bone turnover and fracture risk by 30-50%. Also relieves menopausal symptoms.
Potential risks: Increased risk of blood clots, stroke, breast cancer, and endometrial cancer.
What factors determine the choice of osteoporosis treatment?
The choice of osteoporosis medication depends on several factors:
- Age – Advanced age increases fracture risk and the need for treatment.
- Sex – Medication risks and benefits differ between men and women.
- Severity of osteoporosis – More severe osteoporosis requires more potent treatments.
- Prior fractures – Presence of previous fractures indicates high risk requiring treatment.
- Medication efficacy – The ability of the medication to reduce fracture risk.
- Medication risks – Safety considerations based on medical history.
- Medication cost – Expense and insurance coverage of medications.
- Patient preferences – Route of administration, frequency of dosing.
Treatment guidelines provide recommendations based on a patient’s specific risk factors and characteristics. The goal is to provide maximal fracture prevention while minimizing medication side effects.
What is the duration of osteoporosis treatment?
Most medications for osteoporosis are intended for long-term use to maintain BMD gains and reduced fracture risk. Recommended duration of treatment is:
- Bisphosphonates – 3-5 years or longer based on fracture risk and BMD response.
- Denosumab – Ongoing treatment for continued efficacy.
- Raloxifene – Ongoing based on BMD response and fracture risk factors.
- Teriparatide – Limited to 2 year maximum duration.
- Abaloparatide – Limited to 2 year maximum duration.
- Romosozumab – 1 year followed by antiresorptive therapy.
- Hormone therapy – Shortest duration appropriate for symptom relief.
Periodic assessment of fracture risk helps determine if continued treatment is beneficial. A “drug holiday” may be appropriate after several years of bisphosphonate use to reassess. Treatment may then resume based on updated fracture risk.
What are the adherence rates to osteoporosis medications?
Adherence to osteoporosis medications is suboptimal. Studies show adherence rates are:
- Bisphosphonates – Approximately 50% at 1 year, declining to 35% at 3 years.
- Denosumab – Approximately 80% at 1 year.
- Raloxifene – Approximately 56% at 1 year.
- Teriparatide – Approximately 79% at 1 year.
The high frequency of oral bisphosphonate dosing contributes to poor long-term adherence. IV bisphosphonates and denosumab have better adherence given less frequent dosing.
Reasons for non-adherence include side effects, cost, inconvenience, lack of motivation, and inadequate patient education. Improving adherence is an important priority for optimal fracture reduction.
What are the recommendations for calcium and vitamin D in osteoporosis treatment?
Adequate calcium and vitamin D are essential adjuncts to pharmacological therapy for osteoporosis:
- Recommended dietary calcium intake is 1200 mg per day for adults over age 50.
- Calcium supplements can help meet needs if dietary intake is inadequate.
- Recommended vitamin D intake is 800-1000 IU per day for adults over age 50.
- Vitamin D supplements are often required to achieve optimal blood levels.
Ensuring adequate calcium and vitamin D helps maximize the effectiveness of osteoporosis medications. Deficiencies impair the skeletal response to therapy.
How often is BMD monitoring needed on osteoporosis treatment?
Guidelines recommend BMD testing every:
- 1-2 years when initiating osteoporosis treatment
- 2 years during bisphosphonate treatment
- 1 year during teriparatide or abaloparatide treatment
More frequent BMD monitoring helps assess response to treatment. If BMD remains stable or increases, treatment is likely effective. Declining BMD may prompt medication adjustment or reconsideration of diagnosis.
Vertebral imaging is also recommended every 1-2 years to detect new vertebral fractures, which would indicate treatment failure.
When is a “drug holiday” appropriate from osteoporosis medications?
A “drug holiday” may be considered after 3-5 years of bisphosphonate treatment under certain circumstances:
- Evidence of low fracture risk and minimal bone loss on therapy
- No new fractures during treatment period
- BMD stable or increasing on treatment
- No very high risk factors such as recent major fracture
A holiday allows reassessment of fracture risk after several years of treatment. Holidays are generally not recommended with denosumab due to rapid BMD loss upon discontinuation.
Frequent monitoring of BMD and fracture risk factors is necessary during a drug holiday to determine if treatment should resume.
What are emerging and experimental treatments for osteoporosis?
Emerging and experimental osteoporosis treatments include:
- Romosozumab – FDA approved in 2019, with more data pending on long-term safety.
- Abaloparatide – Approved for use in some countries outside the U.S.
- Odanacatib – Cathepsin K inhibitor, clinical development ceased due to stroke risk.
- Toremifene – Investigated for men on androgen deprivation therapy.
- Sclerostin antibodies – In development to stimulate bone formation.
- Combination therapy – Studies ongoing on synergistic combinations.
Other areas of research include improving anabolic effects of exercise, nutritional approaches, bone-targeting nanoparticles, stem cell therapy, and molecular signaling targets.
Conclusion
In summary, the most effective osteoporosis treatments are those proven to significantly reduce fracture rates at common fracture sites like the hip and spine, while maintaining an acceptable safety profile. Potent antiresorptive medications like bisphosphonates, denosumab, and zoledronic acid have demonstrated the greatest reductions in osteoporotic fractures along with a reasonable safety record based on extensive use.
Anabolic agents like teriparatide and abaloparatide show very promising fracture reduction, but have more limited data on long-term safety. The new drug romosozumab has fracture reduction benefits comparable to the best therapies, but longer follow-up is needed to ensure safety.
Treatment choice requires assessing the patient’s fracture risk profile, medical history, and preferences to maximize fracture prevention while minimizing adverse effects. Adequate calcium, vitamin D, and exercise are key adjuncts to pharmacological therapy. Regular BMD monitoring helps ensure continued treatment efficacy. Further advances in osteoporosis care will require enhancing long-term adherence and developing new therapies with improved effectiveness and safety.