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Treatment for Osteoporosis
Mathematically, density is defined by mass divided by volume. It is a critical factor in the context of osteoporosis—a quantitative disease in which patients have low bone density. Osteoporosis can increase patients’ risk of fragility fractures and lead to a decreased quality of life (Figure). One way of preventing osteoporosis is by achieving and maintaining a healthy peak bone mass. Patients can improve their bone density through various interventions including good nutrition (with an adequate intake of calcium, phosphorus, and vitamin D), regular exercise, avoidance of smoking, and limiting alcohol consumption. These protective factors are important for people of all ages. In addition, regular physical exercise can improve spatial coordination in older patients, decreasing their fall risk and risk of fractures.
Risk factors for developing osteoporosis include age (older patients), gender (females), race (Caucasians and Asians), a positive family history, body habitus (thin patients), and menopause. In addition, there are some medications (eg, anti-seizure medications), gastrointestinal conditions, and endocrine disorders that may contribute to the development of osteoporosis. Bone mineral density is most commonly measured by dual energy x-ray absorptiometry (DEXA) at the lumbar spine (L1-4) and hips. This gives a standard deviation score relative to young, healthy, gender-matched controls (T-score). Accordign to the World Health Organization guidelines, a T-score of +1.0 to -1.0 represents normal bone density, a T-score of -1.0 to -2.5 represents osteopenia, while osteoporosis is defined as a T-score ≤-2.5. In patients who are osteopenic or osteoporotic, it is recommended that pharmacotherapy be started to maintain bone density.
When a patient has been diagnosed with osteoporosis, many physicians begin treatment by ensuring that patients are taking an adequate amount of calcium and vitamin D. Studies show a beneficial effect of vitamin D and calcium supplementation in the prevention of fractures.[1-3] Women between the ages of 19 and 50 years should take 1,000 mg of calcium per day. Women aged 51 years or older should take 1,200 mg per day. Women aged 19 to 70 years should take 600 IU of vitamin D daily. Women older than 70 years should take 800 IU of vitamin D daily. Postmenopausal women with osteopenia or osteoporosis should take 1200 mg of calcium and 800 IU of vitamin D daily.[1-3]
The next tier of pharmacologic treatment in osteoporosis includes medications such as calcitonin, raloxifene, bisphosphonates, and aminobisphosphonate. Bisphosphonates and aminobisphosphonates are the drugs of choice for preventing and treating osteoporosis. Bisphosphonates (clodronate, etidronate, tiludronate) work by binding to hydroxyapatite and inhibiting bone resorption by blocking osteoclast action.[4-5] The aminobisphophonates (pamidronate, alendronate, risedronate, ibandronate, and zoledronic acid) are more potent than the simple bisphosphonates.[4-5] Several studies show that the bisphosphonates and the aminobisphosphonates effectively increase bone mineral density and reduce the risk of hip and spine fractures.[4-7] Of note, osteonecrosis of the jaw has been documented as a rare side effect in patients receiving intravenous pamidronate, zoledronic acid, and, less frequently, oral bisphosphonates.[6-7] Raloxifene and calcitonin salmon are alternatives for patients who cannot take bisphosphonates because of contraindications or adverse effects. Given its relatively weak anti-fracture efficacy, calcitonin is generally not considered as first-line therapy for treatment of osteoporosis.
Teriparatide (Forteo), a recombinant parathyroid hormone (PTH) fragment, increases bone mineral density. PTH increases renal calcium reabsorption, enhances intestinal calcium absorption via its effect on 1-hydroxylation of 25(OH)D, and increases bone remodeling.[8-9] The net effect of PTH on skeletal architecture depends on the pattern of exposure. Continuous secretion of PTH decreases bone mass, especially cortical bone. However, intermittent administration of exogenous PTH increases bone mass. Several clinical studies have shown a significant benefit of intermittent subcutaneous PTH on BMD and fracture risk.[8-9]
Treatment with Forteo can be particularly helpful for patients at risk for vertebral or hip fractures because Forteo has a greater impact on trabecular bone formation.[8-9] In a prospective randomized study by Kendler et al, the authors compared Forteo to Risedronate.[10] The authors found that the risk of new vertebral and clinical fractures was significantly lower in patients receiving Forteo than those receiving Risedronate. To avoid bone loss after stopping Forteo treatment, it needs to be followed with antiresorptive treatment. The latest European International Osteoporosis Foundation and European Society for Clinical and Economic Evaluation of Osteoporosis and Osteoarthritis guidelines recommend the use of anabolic treatment first line for patients with very high fracture risk.[8]
A newer osteoporosis medication is Tymlos (abaloparatide). Tymlos is a recombinant PTH analog that is similar to Forteo. It is injected subcutaneously and has similar potential side effects to Forteo. A meta-analysis of 8 studies by Xu et al showed that Tymlos has a protective effect on women with postmenopausal osteoporosis. It reduces the risk for vertebral fractures and increases hip and lumbar spine bone mineral density.[11] In a study by Miller et al, the authors compare Tymlos to a placebo in a prospective, randomized study evaluating postmenopausal women with osteoporosis.[12] The authors found that new vertebral fractures occurred in 0.58% of participants in the abaloparatide group and in 4.22% of those in the placebo group. There was also a group that received Forteo. In the Forteo group, new morphometric vertebral fractures occurred in 0.84%. The incidence of hypercalcemia was lower with Tymlos (3.4%) vs Forteo (6.4%).
Two other newer medications include denosumab (Prolia) and romosozumab (Xgeva). Both of these medications are monoclonal antibodies that have an antiresorptive effect on bone. Prolia is a monoclonal antibody that binds the cytokine RANKL (receptor activator of NFκ B ligand). This has the effect of inhibiting osteoclast maturation, function, and survival. In a study by Cummings et al, the authors compared the effectiveness of Prolia versus a placebo group in preventing new fractures.13 New fracture risk in the Prolia group was 2.3% versus 7.2% in the placebo group. This signifies a decrease of 68% in the Prolia group versus the placebo group. Xgeva is a monoclonal antibody against sclerostin, a natural inhibitor of the Wnt signaling pathway. In a study by Saag et al, the authors compared the efficacy of Xgeva versus oral alendronate in preventing new fractures.[14] In this study, Xgeva was given subcutaneously for 12 months followed by oral alendronate for 12 months. The control group was given 12 months of oral alendronate followed by oral alendronate for another 12 months. After 24 months, the authors noted a 48% lower risk of new vertebral fractures in the romosozumab-to-alendronate group (6.2%) than in the alendronate-to-alendronate group (11.9%). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group and the risk of hip fracture was lower by 38%. These findings suggest that Xgeva may have greater efficacy in reducing the risk of new vertebral, nonvertebral, and hip fractures compared to alendronate. In conclusion, a wide range of pharmacologic options are now available for the treatment of osteoporosis, each with its own unique set of risks and benefits. As the population continues to age, the prevalence of osteoporosis is expected to rise, making it increasingly important for physicians to stay informed about the latest treatment options.
References
1. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992;327(23):1637–1642.
2. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med. 1997;337(10):670–676
3. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003;326(7387):469.
4. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008;83(9):1032-1045.
5. Kavanagh KL, Guo K, Dunford JE, et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci U S A. 2006;103(20):7829–7834.
6. Cremers SC, Pillai G, Papapoulos SE. Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet. 2005;44(6):551–570.
7. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002;346(9):653–661.
8. Hauser B, Alonso N, Riches PL. Review of current real-world experience with teriparatide as treatment of osteoporosis in different patient groups. J Clin Med. 2021;10(7):1403.
9. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434–1441.
10. Kendler DL, Marin F, Zerbini CAF, et al. Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet. 2018;391:230–240.
11. Xu F, Wang Y, Zhu X. The safety and efficacy of abaloparatide on postmenopausal osteoporosis: a systematic review and meta-analysis. Clin Ther. 2024;46(3):267-274.
12. Miller PD, Hattersley G, Riis BJ, et al; ACTIVE Study Investigators. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. JAMA . 2016;316(7):722-733.
13. Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.
14. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or Alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417-1427.
Contributor:
Yu-Po Lee, MD
From UCI Health in Orange County, California.
