March/April 2022

Osteoporosis
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 15 No. 2 P. 10

Health care providers can empower patients through education.

Osteoporosis is a major health concern characterized by decreased bone strength and bone quality. It also increases risk of osteoporotic fractures, which are associated with reduced quality of life due to greater disability and more frequent hospital admission, as well as increased risk of death.1 Optimal management of osteoporosis requires greater awareness of its risk factors, routine screening, and appropriate utilization of osteoporotic medications that improve bone mineral density (BMD) and reduce the risk of osteoporotic fractures.

Prevalence
More than 200 million people worldwide suffer from osteoporosis.2 An estimated 30% of all postmenopausal women in the United States and Europe have osteoporosis, and at least 40% of these women of these women will have one or more fractures in the course of their lives.3 Persons who suffer an initial fracture are at a significantly increased risk of developing new fractures.4 In 2010, there were an estimated 158 million individuals at high fracture risk; by 2040, it’s estimated that this figure will double because of demographic shifts.5

Bone Remodeling
Human bone forms in a process known as modeling and metabolically undergoes continuous remodeling throughout life. Bone remodeling keeps the bone healthy and strong while supplying calcium to the body. In the resorption phase, osteoclasts digest old bone, while during the formation phase, osteoblasts lay down new bone.6 In young adults, there is a balance between bone resorption and bone formation; however, with age, the remodeling process can shift out of balance, resulting in loss of bone structure and strength and increased fracture risk.

Prevention
Osteoporosis prevention must be a priority as the population ages. Successfully improving bone health and mitigating osteoporosis later in life begins with the education of adolescents and young adults about risk factors that contribute to osteoporosis and the burden of fracture risk later in life. Awareness of osteoporosis risk factors can help improve identification of those persons at greatest risk of osteoporosis, allowing for improved screening efforts (eg, BMD scans) and earlier treatment.

Risk Factors
Risk factors for osteoporosis include advanced age, female gender, hyperthyroidism, hypogonadism, dementia, diabetes, rheumatoid arthritis, family history of osteoporosis/fracture, menopause or surgical removal of ovaries, white and Asian ethnicity, and thin body build.

Independent of changes in bone mass, aging increases the risk of fractures, with a 20-year increase in age associated with a four-fold increase in fracture risk.7 Menopause predisposes women to osteoporosis due to declining estrogen levels. Although men can also develop osteoporosis, they are less likely to do so than are women because they don’t experience the sudden drop in estrogen experienced by females during menopause.

Other risk factors include inadequate nutrition, lifestyle choices such as cigarette smoking, excessive alcohol use, weight, lack of exercise, and some medications including glucocorticoids, anticonvulsants, proton pump inhibitors, thiazolidinediones, antidepressants, loop diuretics, vitamin A and synthetic retinoids, antiretrovirals, and chemotherapeutic drugs (eg, methotrexate).

Calcium and Vitamin D
Adequate calcium intake is associated with reduced fracture risk.8 Calcium deficiency contributes to diminished bone density, early bone loss, and increased fracture risk. However, an estimated 90% of women may not receive sufficient calcium and more than 50% of women treated for bone loss have inadequate vitamin D levels.9

The Recommended Dietary Allowance (RDA) for calcium is 1,000 mg per day in adults aged 19 to 50 and men aged 51 to 70. The recommendation increases to 1,200 mg a day for women age 51 and older and for men aged 71 and older.10 Adequate vitamin D is needed to absorb calcium. The RDA for vitamin D is 600 IUs (international units) per day in adults aged 19 to 70. The recommendation increases to 800 IUs a day for adults aged 71 and older.11

Treatment
Appropriate treatment of osteoporosis is essential to help minimize the risk of negative outcomes. Pharmacological treatments aim to slow or prevent the development of osteoporosis, maintain healthy bone mineral density and bone mass, prevent fractures, reduce pain, and maximize the person’s ability to continue with daily life. A combination of preventive lifestyle measures, supplements, and certain medications is often used for those at risk of osteoporosis. Persons with low BMD, particularly those with a history of fracture and osteoporosis or osteopenia, should be considered for pharmacological treatment.

Pharmacological Treatments
Osteoporosis medications are classified as antiresorptives, which specifically target bone resorption, or anabolics, which promote new bone formation. Antiresorptive agents include bisphosphonates, estrogen, raloxifene, calcitonin-salmon, and denosumab. Anabolic agents include teriparatide (Forteo), abaloparatide (Tymlos), and romosozumab (Evenity). The effectiveness of pharmacological treatments for osteoporosis is predicated on patients receiving adequate calcium and vitamin D therapy.

Bisphosphonates
Bisphosphonates are antiresorptive drugs that target areas of higher bone turnover. Bisphosphonates are absorbed by osteoclasts, inducing osteoclast apoptosis and suppressing resorption.12 Bisphosphonates are the most widely prescribed osteoporosis medications and are typically only taken for three to five years to minimize the risk of long-term side effects.

Oral bisphosphonates include alendronate, ibandronate, and risedronate, while zoledronic acid is an IV formulation. Alendronate and risedronate are effective in reducing vertebral and hip fractures, while ibandronate has only been shown to reduce the incidence of vertebral fractures.1 Alendronate reduces spine and hip fractures by approximately 50% over three years in patients with a prior vertebral fracture or in patients who have osteoporosis at the hip.13 Alendronate reduces the incidence of vertebral fractures by 48% over three years in individuals without a prior vertebral fracture. Risedronate reduces the frequency of vertebral fractures by 41% to 49% and nonvertebral fractures by 36% over three years.14

Oral bisphosphonates should not be used in patients with esophageal or upper gastrointestinal disorders, those who have an inability to stay upright for at least 30 to 60 minutes after administration, or those with chronic kidney disease (estimated glomerular filtration rate <30–35 mL/min). Oral bisphosphonates are poorly absorbed and must be taken on an empty stomach first thing in the morning with 8 ounces of water for maximal absorption. After administration, the patient should not have food, drinks, or medications for at least 30 minutes (alendronate, risedronate) or 60 minutes (ibandronate).1

IV zoledronic acid is given by infusion once yearly for treatment and once every two years for prevention of osteoporosis. It is contraindicated in patients with a creatinine clearance <35 mL/min or in patients with acute renal impairment.1 Zoledronic acid reduces the frequency of vertebral fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25% over three years.15

A rare complication of bisphosphonates is a break or crack in the middle of the thighbone. A second rare complication is delayed healing of the jawbone (osteonecrosis).

Denosumab
Denosumab (Prolia) is a monoclonal antibody that increases bone mass by binding the cytokine RANKL, which inhibits the formation, activation, and survival of osteoclasts. It’s given at a dose of 60 mg subcutaneously every six months. Because denosumab may cause hypocalcemia, patients with hypocalcemia must be treated before initiating denosumab.

Denosumab has been shown to be more efficacious than bisphosphonates in increasing BMD among postmenopausal women.16 However, the association is not well established, as a trial examining the risk of any fracture as a secondary outcome found no difference in the fracture risk between denosumab and alendronate within one year of treatment initiation.16 Denosumab reduces the occurrence of vertebral fractures by approximately 68%, hip fractures by about 40%, and nonvertebral fractures by about 20% over three years.17

Similar to bisphosphonates, denosumab can also cause breaks or cracks in the middle of the thighbone and osteonecrosis of the jaw. Persons taking denosumab may need to do so indefinitely, as there could be a high risk of spinal column fractures after stopping the medication.18

Estrogen
For women in menopause, estrogen replacement can help maintain bone density but is generally not a first-line treatment due to increased risk of heart attacks, breast cancer, and blood clots, which can lead to stroke. Estrogen therapy is generally used in younger women or in women whose menopausal symptoms require treatment. Combined estrogen-progestin therapy is approved for the prevention of osteoporosis and has been shown to have a significant reduction in hip fracture. Estrogen-progestin therapy may be indicated in postmenopausal women with persistent menopausal symptoms but increases the risk of breast cancer, stroke, venous thromboembolism, and coronary disease.

Raloxifene
Raloxifene (Evista) is a selective-estrogen receptor modulator that mimics estrogen’s effects without some of the risks associated with estrogen. Raloxifene’s agonistic effects on estrogen receptors increases BMD and bone mass by decreasing bone resorption. Possible side effects include hot flashes and increased risk of blood clots. Raloxifene reduces vertebral fracture risk by about 30% in persons with a prior vertebral fracture and approximately 55% in patients without a prior vertebral fracture over three years. Raloxifene has not been demonstrated to reduce the risk of nonvertebral fractures.1 Because it may have potential beneficial effects on breast cancer risk reduction, raloxifene may be a good choice for osteoporosis when there is also a need for breast cancer prophylaxis. Raloxifene increases the risk of deep vein thrombosis, hot flashes, and leg cramps.

Testosterone
In men, osteoporosis may be linked to an age-related decline in testosterone levels, or hypogonadism. Testosterone’s direct effects via the androgen receptor on osteoblasts promotes trabecular bone formation.19 A meta-analysis of eight trials enrolling 365 men showed that intramuscular testosterone was associated with an 8% gain in lumbar BMD compared with placebo.20

Calcitonin-Salmon
Calcitonin-salmon (Miacalcin) is a hormone that decreases osteoclast activity to slow bone loss in women with low bone mass who are more than five years post menopause. Unlike bisphosphonates and denosumab, calcitonin lacks data showing a reduction in nonvertebral fractures, thus it is not considered first-line treatment for osteoporosis.21 An advantage of calcitonin is its direct analgesic effect on bone pain.22

Teriparatide
Teriparatide (Forteo) is a parathyroid hormone (PTH) analog and potent osteoanabolic that increases absorption of calcium in the intestines, reduces bone turnover, increases formation of new bone, and increases BMD and bone strength. It’s approved for the treatment of osteoporosis in postmenopausal women and men at high risk for fracture. It's given by daily injection under the skin for as long as two years. This medication reduces the rate of vertebral fractures by approximately 65% and nonvertebral fractures by about 53%. Adverse effects of teriparatide include nausea, dizziness, and leg cramps. There may be a potential risk of osteosarcoma, so it should not be given to patients who are at an increased risk of developing osteosarcoma.

Abaloparatide
Abaloparatide (Tymlos) is a newer osteoporosis medication, a human recombinant parathyroid hormone PTHrP(1-34) that acts as an agonist at the PTH1 receptor, resulting in activation of the cyclic AMP signaling pathway in target cells.23 It’s given as a daily injection. Abaloparatide’s anabolic effects on bone increase BMD and bone mineral content, increasing bone strength at vertebral and/or nonvertebral sites. It’s effective in treating osteoporosis in women who have gone through menopause and are at high risk for fractures, who have been intolerant of previous osteoporosis therapy, or for whom osteoporosis treatment has failed to increase bone mass. Abaloparatide should not be taken for more than two years. Abaloparatide causes osteosarcoma in rats but it is unknown if the risk is the same in people. Persons taking abaloparatide may experience orthostatic hypotension and may feel dizzy, have a faster heartbeat, or feel lightheaded soon after the injection is given, with symptoms generally going away within a few hours. Abaloparatide can also cause hypercalcemia and hypercalciuria.

In a clinical trial, all women with osteoporosis received daily calcium and vitamin D supplements. The patients were then randomly assigned to receive either abaloparatide or placebo for 18 months. Only 0.6% of women receiving abaloparatide experienced fractures, while 4.2% of women receiving placebo experienced fractures. After 25 months of treatment, fractures occurred in 0.6% of women taking abaloparatide and 4.4% of women taking a placebo.24

Benefits in BMD were also noted. At 18 months, women taking abaloparatide had BMD of the spine increase by 9.2%, BMD of the hip increase by 3.4%, and BMD of the femoral neck (where thigh bone meets the hip bone) increase by 2.9%. After taking placebo for 18 months, BMD of the spine increased by 0.5%, BMD of the hip decreased by 0.1%, and BMD of the femoral neck decreased by 0.4%. After 25 months of treatment, women taking abaloparatide had BMD of the spine increase by 12.8%, BMD of the hip increase by 5.5%, and BMD of the femoral neck increase by 4.5%. After taking placebo for 25 months, BMD of the spine increased by 3.5%, BMD of the hip increased by 1.4%, and BMD of the femoral neck increased by 0.5%.24

Romosozumab
Romosozumab (Evenity), approved in 2019, is the newest bone-building medication to treat osteoporosis. It is a humanized monoclonal antibody that promotes bone formation and inhibits bone resorption by inhibiting sclerostin, a protein involved in the regulation of bone formation.25,26 One dose consists of two injections, one immediately following the other, given once a month by a health care professional. Romosozumab’s bone forming effects wane after 12 doses, so more than 12 doses should not be used. If osteoporosis therapy is needed after the 12 doses, patients should begin an osteoporosis treatment that reduces bone breakdown.

Romosozumab is indicated for women with a history of osteoporotic fracture and/or multiple risk factors for fracture, and those who have failed or are intolerant to other osteoporosis therapies.25,26 Careful patient selection is necessary, as romosozumab may increase the risk of heart attack, stroke, and cardiovascular death and should be avoided in patients who have had a heart attack or stroke within the previous year.26 Common side effects of romosozumab include injection site reactions, joint pain, and headache.

The safety and efficacy of romosozumab were demonstrated in two clinical trials involving more than 11,000 women with postmenopausal osteoporosis.26 In the first trial, one year of treatment lowered the risk of a new vertebral fracture by 73%. This benefit was maintained over the second year of the trial when romosozumab was followed by one year of denosumab. In the second trial, one year of treatment with romosozumab followed by one year of alendronate reduced the risk of a new vertebral fracture by 50% compared with two years of alendronate alone. Romosozumab followed by alendronate also reduced nonvertebral fractures compared with alendronate alone.

The Influence of Health Care Professionals
Several studies have shown that increased knowledge encourages patients to seek additional information about osteoporosis, leading to lifestyle changes.26 However, patients frequently have a low level of understanding of the role of medications in reducing fracture risk, little knowledge about potential adverse effects of medications, and poor understanding of the causes of osteoporosis.27,28 Health care professionals have an opportunity to improve bone health and osteoporosis treatment by enhancing patient knowledge with each interaction.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
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8. Larsen ER, Mosekilde L, Foldspang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. J Bone Miner Res. 2004;19(3):370-378.

9. Holick MF, Siris ES, Binkley N, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab. 2005;90(6):3215-3224.

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11. Vitamin D: fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements website. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/. Updated August 17, 2021.

12. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85(11):4118-4124.

13. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture intervention trial. JAMA. 1998;280:2077-2082.

14. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int. 2000;11(1):83-91.

15. Lambrinoudaki I, Vlachou S, Galapi F, Papadimitriou D, Papadias K. Once-yearly zoledronic acid in the prevention of osteoporotic bone fractures in postmenopausal women. Clin Interv Aging. 2008;3(3):445-451.

16. Miller PD, Pannacciulli N, Malouf-Sierra J, et al. Efficacy and safety of denosumab vs. bisphosphonates in postmenopausal women previously treated with oral bisphosphonates. Osteoporos Int. 2020;31(1):181-191.

17. Zaheer S, LeBoff M, Lewiecki EM. Denosumab for the treatment of osteoporosis. Expert Opin Drug Metab Toxicol. 2015;11(3):461-470.

18. Noble JA, McKenna MJ, Crowley RK. Should denosumab treatment for osteoporosis be continued indefinitely? Ther Adv Endocrinol Metab. 2021;12:20420188211010052.

19. Mohamad NV, Soelaiman IN, Chin KY. A concise review of testosterone and bone health. Clin Interv Aging. 2016;11:1317-1324.

20. Tracz MJ, Sideras K, Bolona ER, et al. Testosterone use in men and its effects on bone health: a systematic review and meta-analysis of randomized placebo-controlled trials. NCBI Bookshelf website. https://www.ncbi.nlm.nih.gov/books/NBK72539/. Published 2006.

21. Trovas GP, Lyritis GP, Galanos A, et al. A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers. J Bone Miner Res. 2002;17:521-527.

22. Mehta NM, Malootian A, Gilligan JP. Calcitonin for osteoporosis and bone pain. Curr Pharm Des. 2003;9(32):2659-2676.

23. Tymlos (abaloparatide) injection website. https://www.tymloshcp.com/

24. Radius Health, Inc. Highlights of prescribing information: TYMLOS (abaloparatide) injection, for subcutaneous use.  https://radiuspharm.com/wp-content/uploads/tymlos/tymlos-prescribing-information.pdf. Updated December 2021.

25. Paik J, Scott LJ. Romosozumab: a review in postmenopausal osteoporosis. Drugs Aging. 2020;37(11):845-855.

26. FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture. U.S. Food & Drug Administration website. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-osteoporosis-postmenopausal-women-high-risk-fracture. Published April 9, 2019.

27. Sujic R, Gignac MA, Cockerill R. A review of patient-centered post-fracture interventions in the context of theories of health behavior change. Osteoporos Int. 2011;22:2213-2224.

28. Besser SJ, Anderson JE, Weinman J. How do osteoporosis patients perceive their illness and treatment? Implications for clinical practice. Arch Osteoporos. 2012;7:115-124.