ABSTRACT

Despite the health consequences of osteoporosis and the availability of effective treatments, it is under-diagnosed and under-treated. For example, although 90% of patients with hip fractures have osteoporosis, in 2007 only 20% of patients with fragility fractures were evaluated and treated. In a retrospective study of patients with hip fractures, less than 15% of subjects were diagnosed and less than 13% were treated with medications for osteoporosis, including calcium and vitamin D. Fracture patients require evaluation of secondary causes and treatment of osteoporosis to help prevent subsequent fractures. The preceding chapters summarize the pathogenesis and the clinical evaluation of osteoporosis. This chapter will review established therapeutic options and new approaches for the prevention and treatment of osteoporosis. Strategies include both lifestyle and medical approaches to enhance bone strength. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Osteoporosis is a major growing global health problem, resulting in 200 million osteoporotic fractures worldwide each year (1,2). Characterized by reduced bone mass and architectural deterioration, it leads to an increased risk of fragility fractures often occurring with minimal trauma such as falling from a standing height. These fractures rise exponentially with advancing age and most commonly involve the spine, hip or distal forearm. An estimated 1 in 2 women and 1 in 4 men aged 50 years and older will suffer a fragility fracture in their remaining lifetime. Hip fractures are the most serious of these fractures, given the high rates of morbidity and mortality. Approximately 50% of patients who sustain a hip fracture lose the ability to walk independently and 12-24% of women suffering a hip fracture die within the 1^st year, compared to 33% of men (3-5). Vertebral compression fractures are the most common osteoporotic fractures, but they are often asymptomatic and found incidentally on imaging done for other reasons. Vertebral fractures are, however, associated with high rates of morbidity involving height loss, kyphosis, restrictive lung disease, back pain, and functional impairment. Vertebral fractures are associated with a 5-fold increased risk of future vertebral fractures and a 2 to 3-fold risk of other fragility fractures. Although there are very effective treatments to reduce fracture risk, only 30% of patients with fragility fractures have a bone density test and/or are treated for their underlying osteoporosis. There are currently critically needed national and international efforts to improve fracture care and bone health in women and men. Identification of osteoporosis at the time of a hip, spine, or other fragility fracture is imperative so that patients with fragility fractures can be evaluated for secondary causes of osteoporosis and treated with osteoporosis medications for their underlying bone disease.

The preceding chapters summarize the pathogenesis and the clinical evaluation of osteoporosis. This chapter will focus on reviewing established therapeutic options and new approaches for the prevention and treatment of osteoporosis. Strategies include both lifestyle and medical approaches to enhance bone strength and reduce fractures.

PATHOPHYSIOLOGY

Bone is a dynamic organ with continuous remodeling occurring as osteoclasts resorb bone and osteoblasts form new bone. Among the key regulators of this process is the receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. Interaction between RANKL, produced by the osteoblast lineage, and RANK receptor stimulates osteoclastic differentiation and activity; OPG, made by osteoblasts, is an endogenous decoy receptor that binds with RANKL, inhibiting bone resorption. In addition, the Wnt signaling pathway is involved in activation of transcription of genes that direct the differentiation and proliferation of osteoblasts. In the skeletal life cycle, there is acquisition of peak bone mass during adolescence and young adulthood. For women, bone loss is accelerated surrounding the time of menopause with decreases in bone mineral density (BMD) of approximately 2-3%/year. With advancing age, the decline in BMD occurs at a slower rate of approximately 0.1 to 0.5% per year in women and men.

DIAGNOSIS

BMD testing is typically measured in the proximal femur and lumbar spine, though the distal radius should be measured in patients with hyperparathyroidism or in those in whom the other major sites cannot be adequately assessed. Each SD below peak bone mass represents approximately 2-fold increase in fracture risk. Osteopenia is present when the BMD is between 1.0 and 2.5 SDs below bone density of young healthy individuals. More than 50% of fragility fractures occur in these patients (6). Osteoporosis is defined as a BMD≤-2.5 SDs of young normal, healthy individuals.

Vertebral imaging by DXA or X-ray is useful for identification of spinal fractures that frequently are not clinically evident. The Bone Health and Osteoporosis Foundation (BHOF, previously the National Osteoporosis Foundation) currently recommends DXA for women ≥65 years and men ≥70 years, or earlier if clinical risk factors are present. Physicians should routinely perform height measurements preferably with a stadiometer as there is an association between height loss and spinal fractures. The BHOF Clinical Guide recommends vertebral imaging for spinal fractures in the presence of height loss of 1.5 inches or more and longitudinal height loss of 0.8 inches or more for postmenopausal women and men age 50-69. Vertebral imaging is also recommended in women and men age 70 and 80 years and older, respectively (7). When the diagnosis of a low bone density compared with age-adjusted controls or osteoporosis is made, a work-up to look for secondary causes of osteoporosis should be considered. See Table 1.

Laboratory evaluation may include the following: Calcium, phosphorus, liver function tests (including alkaline phosphatase), complete blood count, 25-hydroxyvitamin D, 24-hour urine calcium +/- PTH, TSH (if clinical evidence of hyperthyroidism or those already on thyroid hormone replacement), and serum testosterone in men. For select cases, one may consider sending specialized tests for gastrointestinal disorders (tissue transglutaminase with an IgA level for celiac sprue), infiltrative diseases (serum tryptase for mastocytosis), neoplastic (serum and urine protein electrophoresis), or excess glucocorticoid (cortisol levels, dexamethasone suppression test for Cushing’s syndrome).

To quantify an individual’s absolute fracture risk, the World Health Organization (WHO) developed the FRAX^® calculator (http://www.shef.ac.uk/FRAX), an integrative measure of various risk factors and femoral neck bone mineral density. In addition to BMD, the following risk factors are included - ethnicity, age, BMI, prior fracture history (designated as a previous fracture in adult life that occurred spontaneously or a fracture arising from trauma, which in a healthy individual would not have resulted in a fracture), glucocorticoid use, excessive alcohol (≥3 units per day), smoking, rheumatoid arthritis, and certain secondary causes of osteoporosis. These secondary causes include Type 1 diabetes, osteogenesis imperfecta, long-standing hyperthyroidism, hypogonadism, premature menopause, malnutrition, malabsorption, or liver disease. If the 10-year absolute fracture risk is ≥3% for hip fractures or ≥20% for other major osteoporotic fractures, pharmacologic therapy should be considered (7). The FRAX^® calculator should be utilized in postmenopausal woman ≥ 40 years and men ≥ 50 years with osteopenia. Although there are data analyzing the use of FRAX^® in patients who have been treated with osteoporosis medications, its use is not currently validated for patients currently or formerly treated with pharmacotherapy for osteoporosis. Additionally, the FDA has approved the use of trabecular bone score (TBS), a structural measure derived from spinal bone density images that is associated with bone microarchitecture and fracture risk. Combining TBS and the FRAX score may increased the predictive value of the absolute fracture risk assessment (8).

Although the FRAX^® calculator has greatly enhanced treatment of osteopenic women and men at risk for fractures, certain risk factors predictive of fracture risk are not accurately measured in this calculator. Patients on chronic glucocorticoids may warrant treatment earlier or at a lower threshold than determined by FRAX^®; further, this tool does not include current or cumulative glucocorticoid doses or duration of treatment (9). Also, of note, spine BMD is not included in the algorithm. Once an initial bone density is measured, a follow-up BMD should be done 1-2 years after the initial screening depending on whether pharmacologic therapy was initiated. Biochemical bone turnover markers, collagen breakdown products, (e.g., N-telopeptide, C-telopeptide) may be helpful in select patients as an indicator of skeletal remodeling or to determine patient’s adherence to treatment.

EXERCISE

While pharmacological therapies are a major focus of this chapter, exercise and strategies to strengthen muscles and prevent falls are important components of osteoporosis care. Skeletal loading and mechanical loads from muscle forces have important effects on bone strength (10). Meta-analyses and clinical investigations have shown that exercise produces modest increases in BMD often ranging between 1% and 3% (11). Physical activity helps to maximize BMD during adolescence and young adulthood, diminish bone loss during aging, and improve stability and strength to minimize falls and fractures in the elderly (11-14). However, these benefits come from slow skeletal adaptations to training over time. Because it takes three to four months to complete the bone remodeling cycle of bone resorption, formation, and mineralization, a minimum of at least six to eight months of an exercise intervention is likely required to achieve a change in bone mass that is quantifiable (15,16). The benefits of exercise are lost when people stop exercising, therefore lifelong physical activity at all ages is strongly endorsed by the BHOF. Exercise recommendations generally should include weight-bearing, muscle-strengthening, and balance training exercises for 30 minutes 5 days per week or 75 minutes twice weekly, often consistent with other general health recommendations. Weight-bearing exercises are activities that make the body move against gravity such as walking, jogging, dancing, tennis, and Tai Chi. To protect the spine in patients with low spinal bone density, maintaining a straight spine and avoiding arching and twisting are generally recommended.

CALCIUM

Adequate calcium intake is essential to prevent calcium mobilization from the bone where 99% of calcium is stored. The effects of calcium supplementation on bone depend on age, menopausal status, calcium intake, and vitamin D sufficiency. Increased calcium intake is necessary during acquisition of peak bone mass and with advancing age. Calcium has modest effects on bone density (17). It is ineffective or minimally effective for prevention of bone loss in women within five years of menopause when there may be predominant effects of estrogen deficiency and other hormonal changes.

The Institute of Medicine's recommendations for daily calcium intake that meet the requirements of 97% of the population are shown in Table 2 (18). Unless a patient has an underlying disorder of calcium homeostasis, the upper limit of safety is considered 2,500 mg for adults aged 19 to 50 years and 2,000 mg for those >50 years (19). As maximum absorption of elemental calcium is about 500 to 600 mg at once, calcium intakes need to be divided into multiple doses throughout the day.

Obtaining calcium through the diet is preferred. While dairy products contain the largest amount of endogenous calcium, many foods including juices, cereals, and cereal bars, may contain added calcium. An 8-ounce glass of milk or calcium-supplemented orange juice contains ~300 mg of elemental calcium, calcium-supplemented soy and almond milk contains ~450 mg, one ounce (or 1 cubic inch) of cheese contains ~200 mg, and certain cereals contain as much as 1000 mg. It is important for physicians to calculate the dietary calcium intake. Resources helpful for patients to calculate their calcium intake include the U.S. dairy council of California website, http://www.healthyeating.org/Healthy-Eating/Healthy-Eating-Tools/Calcium-Quiz.aspx?action=quiz, the International Osteoporosis Foundation website, https://www.iofbonehealth.org/calcium-calculator, and the NOF Clinical Guide also available on the website https://link.springer.com/article/10.1007/s00198-021-05900-y (7). The former allows patients to check off the type and quantity of calcium-containing foods they usually consume and then calculates total daily calcium, with suggestions on how to increase calcium intake to recommended levels. The latter provides an easy tool to calculate calcium intakes from calcium-rich, dietary sources.

Supplemental calcium should be used if an individual’s dietary calcium intake does not meet the recommended daily calcium intake. Calcium carbonate contains 40% of elemental calcium and is a commonly used calcium supplement (e.g., Tums™, Oscal™, Caltrate™, and generic preparations). Calcium carbonate should be taken with food because patients with achlorhydria (or those on proton pump inhibitors chronically) cannot absorb this calcium salt well on an empty stomach (20). Adverse effects of calcium carbonate may include bloating and constipation. Calcium citrate (e.g., Citracal™), which contains 24% elemental calcium, is more bioavailable than calcium carbonate, can be taken while fasting and as a result is the formulation suggested when patients are on proton pump inhibitors chronically.

There have been a number of concerns related to the use of supplemental calcium and the risk of kidney stones and cardiovascular disease. Data from epidemiologic research and clinical trials suggest that vitamin D reduces the incidence of fractures and may also prevent falls and declining physical function, yet the available data are not consistent (21). Data from the Women’s Health Initiative (WHI) calcium and vitamin D clinical trial (CT) of supplemental calcium (1000 mg daily) plus vitamin D (400 IU daily) versus placebo in 36,282 women showed a 17% increased risk of developing renal stones in those assigned calcium plus vitamin D. However, among those compliant with the calcium plus vitamin D regimen versus placebo, there was a 29% reduced risk of hip fracture over seven years (22). Some evidence suggests that calcium supplements but generally not dietary calcium may be associated with vascular calcifications and an increased risk for myocardial infarction (23). In a prospective study in the National Institutes of Health AARP Diet and Health Study of 388,229 women and men in whom baseline calcium intakes were ascertained after an average of 12 years of follow-up, supplemental but not dietary calcium intakes were associated with excess cardiovascular death in men but not women; adverse cardiovascular effects were only observed among smokers (23) (24). An analysis of the WHI randomized placebo-controlled calcium and vitamin D trial (CT) and the WHI prospective observational study (OS) showed that in the CT, in postmenopausal women who did not take supplemental calcium and vitamin D at baseline, supplemental calcium (1000 mg/day) and vitamin D (400 IU/D) versus placebo for ≥ 5years was associated with a 38% reduction in the risk of hip fracture. In a combined analysis of data from the CT and OS, supplemental calcium and vitamin D reduced the risk of a hip fracture by 35%. In these subset analyses of the large WHI, it is important to note that there were no adverse effects of supplemental calcium plus vitamin D on risks of myocardial infarction, stroke, or other cardiovascular disease (25). Although additional analyses are ongoing, calcium intakes within the ranges recommended by the IOM appear not to increase cardiovascular risk.

Recently, however, the United States Preventive Services Task Force (USPSTF) recommended against supplemental calcium (≤1000 mg/day) and low-dose vitamin D (≤400 IU/D) in healthy postmenopausal women due to lack of evidence of benefit in fracture reduction and evidence for increased risk of kidney stones. Thus, the risk of renal stones with calcium supplementation needs to be balanced with fracture reduction. These recommendations did not apply to adults with osteoporosis or vitamin D deficiency (22,26).

VITAMIN D

Vitamin D insufficiency and deficiency is a common problem in many individuals. Individuals at increased risk for low vitamin D levels include the elderly and those with low vitamin D intake, malabsorption, inadequate sunlight exposure, use of sunblock, dark skin pigment, obesity, chronic kidney disease, and use of medications that increase the metabolism of vitamin D. Vitamin D deficiency and insufficiency are common in adults with hip fractures (30,31). Vitamin D deficiency can lead to reduced calcium absorption, secondary hyperparathyroidism, and increased risk of fractures (30,32-34). Mild vitamin D insufficiency may not cause symptoms, but contributes to low bone mass. Severe vitamin D deficiency causes osteomalacia. In addition, although more data are needed, vitamin D deficiency has been associated with proximal muscle weakness, impaired physical performance, increased risk of falls, and possibly increased risks of some cancers (including colorectal, breast among others) (19,35-41). Deficient levels of vitamin D are generally defined as a 25-(OH) vitamin D <20 ng/ml, relative insufficiency as 21 to 29 ng/ml, and sufficient levels of vitamin D to prevent the rise in parathyroid hormone levels as a 25-(OH) vitamin D ≥ 30 to 32 ng/ml (42). The National Health and Nutrition Examination Survey (NHANES) report showed that 32% of Americans have vitamin D deficiency (43).

Sources of dietary intake of vitamin D are limited and these include vitamin D-fortified milk and some soy milks (100 IU/glass), certain cereals, egg yolk, and oily fishes (e.g., salmon, mackerel, and sardines). Multivitamins typically contain 400 IU to 1,000 IU of vitamin D₃, and many calcium preparations are supplemented with vitamin D. The NOF recommends 800 to 1000 IU vitamin D daily for adults aged 50 years and older, as do the International Osteoporosis Foundation and Endocrine Society (44,45). The IOM Committee report on the Dietary Reference Intakes for 97.5% of the population in North America was 600 IU/d of vitamin D for children and adults until age 70 and 800 IU/day for adults 71 years and older (46).

The USPTF recommended supplemental vitamin D for reduction in fall risk in women aged 65 and older. Although a meta-analysis of 31,022 individuals indicated that the highest quartile of vitamin D intakes (median 800 IU (and range 792 to 2000 IU/d) was associated with a 30% and 14% reduction in the risks of hip fractures and non-vertebral fractures, respectively, the USPSTF reported that recommendations concerning the safety and efficacy of higher doses of vitamin D on fracture reduction await additional research (26,27).

In the Vitamin D and Omega-3 Fatty Acid trial, a large randomized, placebo-controlled trial in 25,874 women and men across the United States of the effects of supplemental 2000 IU/d of cholecalciferol versus placebo determined the effect on the primary prevention of cardiovascular, fractures, cancer and other health outcomes. In addition, detailed in-person visits in a sub cohort provide extensive information on effects of supplemental vitamin D and/or omega-3 fatty acids on cardiovascular outcomes, bone health and many other clinical outcomes (28,29). This study found that in general, in a healthy population not preselected for low vitamin D levels or osteoporosis, supplemental vitamin D had no effect on bone density or bone structural measures or incident falls or fractures (194,195,196).

Patients with vitamin D deficiency need much higher doses. The upper limit of safety for vitamin D is 4000 IU/day. There are currently differing recommendations regarding the optimal 25-hydroxyvitamin D (25-OHD) level for bone health with the IOM committee recommending a 25-OH D level ≥20-29 ng/mL while several other societies recommend a 25-OHD level ≥30 ng/mL (44,45).

In the presence of vitamin D deficiency, it is safe to normalize vitamin D levels to a 25-(OH)D level of 30 ng/ml to prevent the compensatory rise in parathyroid hormone (PTH) level (33,47). This may be done in a variety of ways. High doses of vitamin D may be needed [e.g., 50,000 IU of D₂ (ergocalciferol) or equivalent dose of D₃ (cholecalciferol) weekly for 8 weeks or according to the 25-hydroxyvitamin D level] (45). Individuals with malabsorption often require very high doses of supplemental vitamin D, and may benefit from evaluation by a bone specialist.

TREATMENT AND/OR PREVENTION OF OSTEOPOROSIS

There are effective therapies for osteoporosis and promising therapeutics under development. The antiresorptive therapies that reduce bone turnover include: bisphosphonates; estrogen or hormone therapy, estrogen agonists/antagonists [selective estrogen-receptor modulators (SERMs)]; calcitonin; and denosumab, a human monoclonal antibody to RANK-ligand. At present there are two FDA-approved anabolic or bone forming osteoporosis therapy, teriparatide [PTH (1-34)] and abaloparatide. Romosozumab is a monoclonal antibody to sclerostin and stimulates bone formation and inhibits bone resorption. In selection of the optimal therapy for a given individual, it is important to consider patient preference, cost, mode of administration, duration of treatment, and the effects of a treatment on reduction of spine, hip and other non-spine fractures. Tables 4 and 5 lists the currently available osteoporosis drugs approved by the FDA, their dosage, indication, and general efficacy for fracture reduction.

HORMONE REPLACEMENT THERAPY

In postmenopausal women, it is well known that estrogen therapy (ET) and hormone therapy [estrogen plus progesterone (HT)] prevent bone loss and increase BMD through interaction with estrogen receptors on bone cells, activation of tissue-specific genes and proteins, and/or a reduction in cytokines that stimulate osteoclast function (51-54). In addition to the bone density benefit, the Women’s Health Initiative (WHI) did show that HT resulted in a 34% reduction in the risk of hip fractures and clinical spine fractures (55). However, the risks – increases in breast cancer, coronary heart disease (CHD), pulmonary embolism (PE), and stroke, outweighed the benefits. In addition, after cessation of ET or HT, the benefit of fracture reduction is not sustained (56,57). Although data from the WHI show that ET and HT reduce fractures, ET and HT are FDA-approved for the prevention of fractures but not for the treatment of osteoporosis (55,58). Data has shown potential cardiovascular safety with use of ET in early menopause, though this remains controversial (the “critical window” hypothesis) (59-61).

Unlike oral estrogens, in postmenopausal women transdermal estrogens do not adversely affect clotting factors, and are therefore preferred. Transdermal estrogens prevent bone loss and are available in low doses (e.g., 0.014 to 0.0375 mg daily patch applied 2x/week). In women with premature or early menopause, hormone replacement can be considered until the natural age of menopause (51.3 years) (62). Before estrogen is prescribed, the benefits versus the risks of cardiovascular disease, stroke, and breast cancer should be reviewed. When prescribing estrogen, the FDA recommends the following: consider all non-estrogen preparations first for osteoporosis prevention; use the lowest dose of HT/ET for the shortest time interval to achieve therapeutic goals; and prescribe HT/ET when benefits outweigh risks in a given woman.

CALCITONIN

Calcitonin is a 32-amino acid peptide produced by the parafollicular cells of the thyroid that inhibits bone resorption through direct effects on the osteoclasts. Calcitonin is a highly conserved protein, with human and salmon calcitonin differing by only one amino acid. Injectable salmon calcitonin was approved by the FDA in 1984 for the treatment of osteoporosis, although current use is limited because of the availability of other more effective medications for the treatment of osteoporosis. Calcitonin nasal spray (Miacalcin™ and Fortical™ 200 IU daily) is a form of calcitonin (70) approved by the FDA for the treatment of osteoporosis in women more than five years past menopause. Although studies have shown calcitonin nasal spray to decrease spine fractures, there is no effect on the prevention of hip and other non-spine fractures. Current and future use of calcitonin for osteoporosis has been limited, however, because of data analyses showing a potential increased risk of cancers, particularly liver cancer with calcitonin use, though this remains controversial (71). An FDA review found no causal relationship between calcitonin use and cancer but cautioned that physicians should evaluate the potential benefit to relative risk of calcitonin use in patients.

BISPHOSPHONATES

Bisphosphonates are analogs of pyrophosphate that inhibit bone turnover and because of their phosphorous-carbon-phosphorous structure are resistant to hydrolysis. They have a strong affinity for calcium crystals and bind avidly to the surface of bone. Bisphosphonates suppress bone resorption and interrupt osteoclast activity directly through several mechanisms including inhibition of acid production, lysosomal enzymes, and the mevalonate pathway (72-74) and indirectly through their effects on osteoblasts and macrophages. They also inhibit osteoclast recruitment and induce osteoclast apoptosis. Thus, through various mechanisms, bisphosphonates reduce the depth of resorption pits (thereby producing positive bone balance at individual bone remodeling units) and decrease the formation of new bone remodeling units.

DENOSUMAB

Denosumab is the first FDA-approved human monoclonal antibody that binds to the receptor activator of nuclear factor kappa B ligand (RANKL), an important regulator of bone remodeling. RANKL is secreted by osteoblast precursors and binds to its receptor, RANK, located on osteoclasts. Osteoprotegrin is an endogenous cytokine and decoy receptor that binds RANKL and inhibits osteoclast activation (154). The binding of RANKL to RANK promotes osteoclast proliferation, differentiation, activation, and survival. Denosumab inhibits RANKL and osteoclastogenesis and markedly reduces bone resorption.

PARATHYROID HORMONE

ROMOSOZUMAB

Romosozumab is a monoclonal antibody to sclerostin, a potent inhibitor of osteoblast differentiation and bone formation by way of Wnt signaling inhibition. Animal studies show that blocking the effect of sclerosin was associated with large increases in bone mass. In phase II trials, romosozumab administration shows increased BMD at the spine of 11.3%, as well as increased bone formation and decreased bone resorption (193). A dual effect of transiently increasing markers of bone formation (P1NP) while simultaneously lowering marker of bone resorption (CTX) was also demonstrated in the phase II trial.

GLUCOCORTICOID-INDUCED OSTEOPOROSIS

Glucocorticoid induced osteoporosis (GIO) affects the spine greater than other sites. The 2010 American College of Rheumatology (ACR) guidelines can be used to help clinicians determine appropriate therapeutic options in those on glucocorticoid therapy (181). Epidemiological data has consistently shown that those taking glucocorticoids have fractures at higher T-scores. Glucocorticoids not only increase bone resorption, but also reduce bone formation. Thus, there are two important steps for targeted intervention—bisphosphonates and teriparatide, respectively. Rapid bone loss is prevalent in the first 6-12 months of glucocorticoid therapy; however, the increased fracture risk is already present within 3 months of initiating glucocorticoids. Thus, bone protection therapy should be started, at the onset, if the duration of glucocorticoids is anticipated to be 3 months or longer. For postmenopausal women and men over age 50, treatment for GIO is determined based on whether the patient’s risk for fracture—using FRAX® and clinical judgment—is low (<10%), moderate (10-20%), or high (>20%). For those taking prednisone dose >7.5 mg/day, the FDA has approved the following bisphosphonates—Risedronate, Alendronate, Zoledronate—and the anabolic agent, Teriparatide, for the treatment of GIO. In a 3-year randomized trial evaluating the prevention and treatment of GIO, teriparatide was statistically superior to alendronate in preventing BMD declines at the spine and hip (182).

CONSIDERATIONS REGARDING SELECTION OF ANTI-FRACTURE TREATMENT

When approaching a patient at high risk for fracture, several considerations may help guide the initial treatment selection. Anabolic agents (i.e., romosozumab, abaloparatide, or teriparatide) should be considered as first-line agents In patients deemed “very high risk” for fracture. This may include patients with very low T-scores <-3.0 at the lumbar spine or hip, recent fragility fracture, multiple risk factors for fractures or fractures while on approved osteoporosis therapy or intolerance to osteoporosis therapies. If anabolic treatment is contraindicated or not available for a patient, a parental anti-resorptive agent should be considered.

Denosumab can also increase bone density and reduce fracture risk in women and men at high risk for fracture. Denosumab is FDA approved to treat glucocorticoid-induced osteoporosis in men and women at high risk for fracture, in women at high fracture risk on adjuvant aromatase inhibitor therapy for breast cancer, and in men treated with androgen deprivation for prostate cancer.

In patients with advanced chronic kidney disease, treatment options can be limited. Bisphosphonates are generally contraindicated in those with eGFR <30-35. Denosumab (Prolia) is the preferred agent for those with more advanced kidney disease, given lack of direct renal toxicity and renal metabolism compared to bisphosphonates. However, it is important to note that though denosumab has been shown to improve bone mineral density in those with advanced renal disease, there is little evidence of fracture reduction in this population. Since patients with CKD may have several different types of metabolic bone diseases including osteoporosis, use of denosumab should be approached with caution given the increased complexity of bone disease in these patients.

It is important to note that when selecting an anabolic agent or denosumab, a plan for the next agent in their treatment sequence should be considered at the onset. Anabolic agents are approved for 1-2 years of use, thereafter their effects wane. At present use of teriparatide can be used for more than a total of 2 years in patients at high risk of fracture. Anti-resorptive agents should ideally be given after completion of a course of anabolic in order to prevent the bone loss that occurs with discontinuation of these therapies. Regarding denosumab, this is approved for 5-10 years of continuous use, but at the point when denosumab is discontinued, it must be followed at the time of first missed dose or just after with an alternative anti-resorptive to prevent rapid rebound bone loss and spine fractures. Ongoing research is assessing different approaches to prevent the bone loss associated with the discontinuation of denosumab. In patients with intolerance or a renal contraindication to using bisphosphonates, the options for the treatment sequence must be taken into account and discussed with the patient as part of shared-decision making.

Zoledronic acid is an appropriate first-line option for several different patient scenarios. As mentioned in the Zoledronic acid (ZA) section above, it is the optimal choice in patients post-hip fracture given the benefit in morbidity and mortality in this setting. ZA should also be considered in patients at high fracture risk who have upper gastrointestinal/esophageal disease, or significant malabsorption (i.e. post-gastric bypass surgery), as oral bisphosphonates may be associated with increased risk of GI intolerance or poor absorption and efficacy, respectively. In patients with compliance difficulties or major transportation concerns, zoledronic acid may also be optimal given its infrequent and flexible dosing (once yearly, though less frequently may also be appropriate in select patients). This is in contrast to denosumab, which requires strict adherence to an every 6 month schedule of injections in order to avoid the consequence of rebound bone loss if doses are missed or significantly delayed.

Lastly, raloxifene may be considered in patients within 10 years of menopause, who are at high fracture risk at the spine, and high risk for breast cancer based on familial history. Otherwise, an oral bisphosphonate (e.g., alendronate or risedronate) or intravenous bisphosphonate or denosumab is preferred over raloxifene as these therapies have been shown to reduce spine and non-spine fractures.

Clinical guides from the Bone Health and Osteoporosis Foundation (7), American Association of Clinical Endocrinologists/American College of Endocrinology (205), and the Endocrine Society (201) provide more detailed information on the management of osteoporosis in high- risk patients.

TREATMENT GAP IN OSTEOPOROSIS THERAPY

Despite having highly effective and well-tolerated available therapeutics for the treatment and prevention of osteoporosis, the rate of treatment of at-risk patients is much lower than desired. Based on prescription databases, bisphosphonate use declined by greater than 50% between 2008 and 2012 (183). In addition, the use of bisphosphonates among those with hip fractures declined from 15% in 2004 to only 3% in 2013, which is concerning given the high risk for future fracture in the setting of hip fracture (139). This decline in use temporally coincides with FDA warnings regarding potential risks related to anti-resorptive use, such as rare atypical femur fracture and osteonecrosis of the jaw, though the FDA has not restricted their use based on these risks (184). It is clear that many patients who would benefit from osteoporosis treatment are not receiving it, and this is a major concern for those who treat osteoporosis. Providers must be able to hold thorough and honest discussions with patients regarding the benefits and risks of osteoporosis treatment options in order for patients to accept and comply with needed treatment.

CONCLUSION

Osteoporosis is a major public health problem that affects approximately 50% of women and 25% of men aged 50 years and older and fractures increase exponentially with advancing age. At present, a number of safe and very effective osteoporosis therapies are available. Antiresorptive agents, such as the bisphosphonates, raloxifene, estrogen (not approved for treatment) and denosumab increase bone density and reduce fractures. Teriparatide, abaloparatide, and romosozumab are anabolic therapies and their treatment effects are best consolidated with an inhibitor of bone resorption such as a bisphosphonate or denosumab. A comprehensive review of the prevention and treatment of osteoporosis is summarized in the 2022 Bone Health and Osteoporosis Foundation Clinician’s Guide (7). A multifaceted approach including calcium and vitamin D, exercise, pharmacologic therapy, and fall prevention strategies can reduce the risk of fractures and promote independent healthy lives in older men and women.

ACKOWLEDGEMENTS

We wish to acknowledge Anjali Grover, MD, Kara Mikulec, MD and Kathryn E. Ackerman, MD, MPH, and thank them for their past contributions to the Endotext chapter and Jill MacLeod for her assistance in preparation of this review.

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