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INTRODUCTION

What constitutes a public health crisis? Public health crises are difficult situations or complex health problems that affect humans in one or more geographic areas and may encompass the entire globe. They generally have significant impact on community health, cause loss of life, and impact the economy adversely.¹ Osteoporosis’s significant global cost, morbidity, and mortality repercussions constitute a public health crisis. Osteoporosis and low bone mass affect roughly 54 million Americans.² Approximately 1 in 2 women and up to 1 in 4 men aged 50 and older will experience a bone fracture because of osteoporosis.²

As a generalized skeletal disorder, osteoporosis compromises bone strength and deteriorates bone quality. Characterized by low bone density, impaired bone architecture, and compromised bone strength, it increases bone fragility and susceptibility to fracture stealthily and silently.³ Affected individuals often develop fractures after little or no apparent trauma. As Healthy People 2020 ended and the nation’s public health advisors prepared Healthy People 2030, the program reported that from 2013 to 2014, 7.3% of adults aged 50 and older had osteoporosis at the hip.⁴ With a 2020 target of 5.3%, our health care system fell short of meeting the goal. Very recently, epidemiologists analyzed the 2005-2008 National Health and Nutrition Examination Survey (which reported an osteoporosis prevalence of 9% overall) to determine if people with prediabetes—estimated to be about one-third of the U.S. population—were at increased risk for lower bone mineral density (BMD), osteopenia, or osteoporosis.⁵ Their results indicate that in U.S. adults older than 40 with prediabetes, these conditions were higher in prevalence at the end of the study period than at the beginning. This indicates increasing prevalence.⁵

This analysis also identified 2 groups at significant risk.⁵ Men younger than 60 and women age 60 years or older were at greatest risk. Moreover, they also observed a growing prevalence of osteopenia/osteoporosis at the femoral neck in adults older than 40 years old with normal glucose regulation.⁵ Although most people identify osteoporosis as a women’s issue, this complex public health issue affects the entire American population. Causing progressive bone loss in affected individuals, it is associated with serious medical consequences, loss of independence, or death as it progresses.

DECLINING TREATMENT RATES

Prescribers employed bisphosphonates liberally for postmenopausal women for treatment and prevention of osteoporosis as soon as the U.S. Food and Drug Administration (FDA) began to approve them.⁶ These drugs are also used for patients with drug-induced bone loss and cancer. However, recent research indicates their use is falling. Economists examined trends in oral bisphosphonate prescriptions and sales, patient and prescriber characteristics, and intravenous bisphosphonate sales for osteoporosis treatment. They found that in 2002, retail pharmacies dispensed approximately 21.3 million prescriptions for oral bisphosphonates in the United States (U.S.). Sales volume peaked in 2007 and 2008, with a 46% increase to 31 million prescriptions. Yet by 2012, sales fell 53% to 14.7 million prescriptions. Intravenous bisphosphonate sales followed a similar trend, growing almost 4-fold from 2007 to 2010, followed by a 22% decrease in 2012.⁶

This study also examined data from an ongoing monthly office-based survey. It found that physicians suggested oral bisphosphonates most often for older white women with lower body mass. These researchers indicate that bisphosphonate use declined substantially over the last 13 years.⁶ A subsequent study also noted decreasing use of bisphosphonates.⁷ Osteoporosis-related fracture rates, which had been declining, have now leveled off.^6-10

In 2016, the American Society for Bone and Mineral Research, the National Osteoporosis Foundation, the National Bone Health Alliance, the Mayo Clinic, and the International Osteoporosis Foundation issued a Call to Action.¹¹ They indicated that osteoporosis treatment is in crisis—clinicians are not prescribing appropriate medications and among patients who have prescriptions, many are nonadherent. It appears that widespread media coverage of lawsuits, large jury awards for rare adverse events (e.g., atypical femur fractures and osteonecrosis of the jaw [ONJ]), and television ads for patients to join class action suits have influenced use of all osteoporosis medications negatively.^12,13 The statistics are startling^14,15:

• Only 23% of older Americans hospitalized for a hip fracture are discharged with a prescription for osteoporosis drugs—this group’s risk for future fracture increases 86% at discharge. Ideally, all of these patients would be treated.
• Physicians failed to inform 96% of postmenopausal women (50 years and older) who had a fracture that it could be osteoporosis-related. Ideally, all should be told.
• One-third of postmenopausal women with a fracture were not referred for follow-up care despite the risk of subsequent fractures. Again, referral should be routine.
• Osteoporosis is one of the ten most costly chronic conditions to treat and the predicted global increase in the prevalence of osteoporotic fractures has elevated osteoporosis to a major public health crisis.

Researchers have noted atypical fractures in rare instances in women using bisphosphonates and denosumab, although the pathophysiology behind these fractures is unclear.^16-19 Experts lament the decline in use of effective medications for osteoporosis. Pharmacists, as accessible and trusted health care providers, can help prospective patients understand the need for treatment.

Pathophysiology

Skeletal bones are not simply “hangers” for skin and organs. Three-quarters of their work is structural (mobility, support, and protection), but they also store calcium and phosphorus.²⁶ Over the years, external physical activity and internal chemical mediators direct modeling and remodeling processes, causing bones to change in shape, size, and position. Specialized cells are key for resorption (bone break down) and formation (bone building); osteoclasts and osteoblasts, respectively, accomplish these functions. Bone resorption typically takes 2 to 3 weeks, but formation may require up to 4 months. When osteoclasts’ and osteoblasts’ functions favor bone resorption over formation, osteopenia and osteoporosis occur.²⁶

Several hormones regulate calcium and phosphorus and thus bone resorption and formation: calcitonin, calcitriol (active vitamin D), cortisol, estrogen, growth hormone, parathyroid hormone, testosterone, and thyroid hormone.²⁶ Communication between osteoclasts and osteoblasts also affects bone resorption and formation. For example, the receptor activator of nuclear factor kappa B ligand (RANKL) is a protein that binds to osteoclast precursors and increases osteoclast activity. In normal bone turnover, osteoblasts produce a protein that binds to RANKL and prevent it from interacting with osteoclast activity. However, patients who have estrogen deficiency produce more RANKL, increasing risk for osteopenia and osteoporosis.²⁶ Sclerostin binds with the Wnt receptor and inhibits the differentiation of precursor cells into mature bone-forming osteoblasts.²⁷

Guidelines and Practice Bulletins

Many professional organizations have compiled practice guidelines for osteoporosis, and for the most part, they are quite similar. However, they differ in subtle ways and this creates confusion for practitioners. In addition, many have not been updated in quite some time or withdrawn. Table 2 lists some popular guidelines, although the list is not comprehensive.

The need for screening is underscored by this disease’s “silence”—it is asymptomatic until late in the disease process and a fracture may be the first sign of trouble. Screening is accomplished using dual-energy X-ray absorptiometry (DXA). In general, radiology technicians use DXA to measure BMD at the femoral neck, total hip, and lumbar spine. Radiologists report DXA scan results as a T-score or Z-score:^22,36  

• The T-score compares an individual’s BMD to young healthy adults’ mean BMD, expressing the results as a standard deviation (SD). A score of 0 means that the individual's BMD is equal to the mean, whereas +1.0 indicates 1 SD above the mean, and -1.0 indicates 1 SD below the mean.
• A Z-score compares the individual's BMD to a matched norm of the same age, gender, and ethnicity. Clinicians do not employ Z-scores to diagnosis osteoporosis or osteopenia because it can remain steady despite declining BMD. A Z-score is most useful for assessing bone health in children and pre-menopausal women.

The World Health Organization (WHO) has classified bone health based on T-score³⁷:

• Normal BMD is a T-score equal to or greater than -1.0.
• A T-score between -1.0 and -2.5 is considered osteopenia
• A T-score less than or equal to -2.5 is considered osteoporosis
• A T-score less than or equal to -2.5 with one or more fractures is considered severe osteoporosis.

BASIC TENETS OF CARE

As with all diseases, prevention is best if possible. Adequate calcium and vitamin D intake is a building block for osteoporosis prevention at any age and supplementation is also needed during treatment programs. Most guidelines also promote exercise, and most importantly, weight-bearing exercise.

Once osteopenia progresses to osteoporosis, treatment is needed. Its goal is prevention of fractures, but no treatment has been proven to eliminate fracture risk.²⁸ In other words, patients who are receiving treatment may experience fractures, but their risk is lower than if they had remained untreated. Risk is greatest after a recent fracture, but the risk falls as time passes.³⁸

Calcium and Vitamin D

While calcium and vitamin D are critical for bone health, they can also be confusing for patients and pharmacy teams. Calcium supplements have varying elemental calcium content. In the U.S., the Supplement Facts panel on over-the-counter calcium supplements lists the amount of elemental calcium. Consider the two most common formulations: calcium carbonate and calcium citrate (see Table 3).

Vitamin D is essential for calcium absorption. Direct skin exposure to sunlight is the best way to obtain vitamin D but many people use sunscreens routinely. Research concerning sunscreen use and vitamin D levels has produced controversy, with some studies indicating sunscreens reduce vitamin D synthesis and others indicating they do not.^40,41 A recent cross-sectional data analysis indicates they do not.⁴⁰ Regardless, vitamin D deficiency is common, even in countries that have ample sunlight year-round. Consuming vitamin D-rich foods (e.g., fatty fish [mackerel, salmon, tuna], and vitamin-D fortified foods [milk, cereal, juice]) is sensible. Guidelines don’t recommend routine vitamin D deficiency screening. However, guidelines do indicate that patients need not take supplemental vitamin D routinely unless their serum vitamin D [25(OH)D] level falls below 30 ng/mL. Vitamin D supplements may interact with cholestyramine, orlistat, statins, steroids, thiazide diuretics, phenobarbital, and phenytoin.⁴²

When recommending calcium or vitamin D supplement use, pharmacists must consider daily dietary intake from dietary sources. Teaching patients to read nutrition labels to determine various foods’ calcium and vitamin D content helps patients, but it is often overlooked.⁴³ Table 3 lists recommended daily intakes.

Some controversy has arisen over concerns about calcium supplementation’s possible associations with cardiovascular (CV) safety issue. No study to date has assessed calcium supplementation and CV risk as a primary outcome; all studies report CV outcomes using secondary data analysis.¹⁸ A 2016 systematic review and meta-analysis found that calcium from dietary or supplement intake at levels within the tolerable upper range (2000 to 2500 mg per day) were not linked to elevated CV risk in generally healthy adults.²¹ Furthermore, the National Osteoporosis Foundation and American Society for Preventive Cardiology published a position statement summarizing moderate-quality evidence. It indicated calcium intake at or below 2000 to 2500 mg daily with or without vitamin D (either from dietary sources or supplementation) has no effect on the risk of CV outcomes, cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults.

DRUG CLASSES

FDA has approved several drugs and biologics for osteoporosis: anabolic agents derived from parathyroid hormone, antiresorptive drugs (selective estrogen receptor modulators, bisphosphonates, denosumab), and a sclerostin inhibitor (romosozumab-aqqg). All effectively reduce risk for vertebral osteoporotic fractures, while alendronate, risedronate, zoledronate, denosumab, and romosozumab-aqqg also reduce the risk for nonvertebral fractures, including hip fractures.⁴⁴ In addition, estrogen and calcitonin are used in select circumstances to address osteoporosis; they will not be discussed here.

Antiresorptives

Bisphosphonates. Bisphosphonates are antiresorptive medications that inhibit osteoclast bone resorption by impairing osteoclasts from forming ruffled borders and decreasing osteoclast development. These drugs have a very long terminal half-life of up to 10 years because they incorporate themselves into the bone.⁴⁵ The FDA has approved 4 bisphosphonates (alendronate, ibandronate, risedronate, and zoledronic acid). Table 4 summarizes the bisphosphonates. Patients must have an adequate intake of calcium and vitamin D (either dietary or supplemental) while taking bisphosphonates. Patients who take oral bisphosphonates must take them exactly as prescribed. In addition, healthcare providers need to remind patients that they should take oral bisphosphonates with a large glass of water. They must not eat or drink anything other than water for 2 hours after taking it. Patients must also sit upright for 30 minutes after taking oral bisphosphonates.^46-49

Patients who take the oral bisphosphonates may experience abdominal pain, nausea, or dyspepsia. Rarely, patients have experienced atypical femur fractures; bone, joint, or muscle pain; dysphagia; esophageal ulceration; or ONJ (progressive destruction and death of bone that affects the mandible or maxilla).^46-49

ONJ has received much media coverage despite an estimated prevalence of 0.001%-0.1%, it’s critical to note that more than 90% of cases have occurred in patients receiving high-dose IV bisphosphonates for cancer.²⁸ Other risk factors for ONJ include longer durations of use, invasive dental procedures, underlying dental pathology, and poor dental hygiene. ONJ has been associated with all antiresorptives, but has been best described with bisphosphonates and denosumab.²⁸ For this reason, patients should have a dental exam at baseline and delay initiation if they need significant dental work. No evidence indicates that stopping therapy changes outcomes, but prescribers and patients should discuss and consider bisphosphonate discontinuation.

Denosumab. Denosumab is also an antiresorptive.⁵⁰ This fully human monoclonal antibody binds to RANKL, blocking its ability to activate the RANK receptor on osteoclasts. This increases osteoclast apoptosis (programmed cell death). It is usually administered by a health care provider as a 60 mg subcutaneous injection every 6 months. Patients need to take calcium 1000 mg once daily and at least 400 IU of vitamin D once daily for the duration of treatment. Common adverse reactions include back pain, arthralgias, cystitis, possible small increase in serious infection (e.g., cellulitis), and eczema. Serious infections, prior dermatologic reactions, ONJ, and atypical fractures are contraindications. Patients who have hypocalcemia or are pregnant should not take denosumab. Denosumab’s effects on bone remodeling reverse after 6 months if it is not taken on schedule.⁵⁰

Raloxifene. Raloxifene is a selective estrogen receptor modulator (SERM).⁵¹ Since estrogen upregulates osteoprotegerin and downregulates RANKL, raloxifene reduces osteoclast formation and increases osteoclast apoptosis. This oral antiresorptive is dosed at 60 mg orally once daily. Common adverse effects include hot flashes, leg cramps, peripheral edema, and a 3-fold increased risk of venous thromboembolism (VTE). A boxed warning in its labeling warns against use in patients with histories of VTE and warns of a small risk for fatal stroke.⁵¹ When using raloxifene for osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate.⁵¹

Anabolic Agents

Teriparatide (20 mcg subcutaneously once daily) and abaloparatide (80 mcg SC injected once daily in women only) are recombinant human parathyroid hormones (PTH).^52,53 Research shows that, unlike endogenous PTH, exogenous PTH in low and intermittent doses increases bone formation without stimulating bone resorption. Subsequently, bone remodeling and osteoblast number and activity increase. Both drugs can be administered for up to 2 years. Here, too, clinicians should assess patients’ calcium and vitamin D intake and supplement if necessary.^52,53

Sclerostin Inhibitor

Romosozumab-aqqg. Romosozumab is a monoclonal antibody that inhibits sclerostin and is given with adequate calcium and vitamin D during treatment.²⁷ Sclerostin binds with specific receptors and inhibits the differentiation of precursor cells into mature bone-forming osteoblasts; blocking sclerostin increases osteoblast activity and stimulates new bone formation. It is indicated for use in post-menopausal women at high risk for fracture (defined as a history of osteoporotic fracture, or multiple risk factors for fracture), and in patients who have failed or are intolerant to other available osteoporosis therapies. It is administered as a 210 mg dose subcutaneously once a month for 12 doses. Two 105 mg/1.17 mL single-use prefilled syringes are required to administer the recommended 210 mg dose.²⁷

Common adverse effects include arthralgia and headache.²⁷ Rarely, patients have experienced myocardial infarction (0.3%-0.8%) or stroke (0.2%-0.6%); these events are described in a boxed warning. Its contraindications include hypocalcemia, which can be corrected before treatment initiation. Prescribers should be cautious about using romosozumab in patients who have had previous major adverse cardiac events, hypersensitivity reactions, ONJ, or atypical femoral fractures.²⁷

Combination therapy is not recommended for osteoporosis for three reasons. No evidence indicates it would be more effective, the medications are costly, and risk for adverse reasons would increase.²⁸

Treatment Duration and Drug Holidays

Drug holidays—treatment interruption for a period of time—are only proposed for the bisphosphonates because of their inordinately long retention in bone. The best available data in support of drug holidays is from alendronate and zoledronic acid studies.⁵⁴ One study suggested that after 3 to 5 years of bisphosphonate therapy, patients with mild to moderate fracture risk may consider discontinuing the medication.⁵⁵ Clinical practice guidelines concur that drug holidays are reasonable after 3 years of IV bisphosphonate or 5 years or oral bisphosphonate.^4,5 Patients at very high risk for a fracture should continue therapy for 6 to 10 years if on oral bisphosphonate, or for 6 doses of IV bisphosphonates.²⁸ Patients should resume therapy if a fracture occurs, BMD decreases, bone turnover markers rise above pretreatment levels, or the patient again meets initial treatment criteria.^55,56

No treatment can completely reverse established osteoporosis, so intervention to prevent osteoporosis is critical. Reversing bone loss in osteoporosis care requires deployment of the entire heath care team. Traditional approaches that focus on training healthcare providers and emphasizing safety among patients are not working. At this point, health care providers need tools that will raise awareness among all parties to the problem. Patients also must be taught how to monitor and change their behavior. Pharmacists are increasingly being trained in motivational interviewing, and have ample contact with high-risk patients.

The recent American College of Physicians clinical practice guideline makes 2 strong recommendations based on high- or moderate-quality evidence, and 4 weaker receommendations⁵⁷:

• Strong: Offer alendronate, risedronate, zoledronic acid, or denosumab to women with known osteoporosis to reduce hip and vertebral fracture.
• Strong: In postmenopausal women, do not use estrogen, estrogen plus progestogen, or raloxifene for the treatment of osteoporosis.
• Weak: In women with osteoporosis, use pharmacologic treatment for 5 years, employing generic drugs when possible.
• Weak: Do not monitor BMD during the 5 years of treatment in women with osteoporosis, as evidence suggests that fracture risk may be reduced regardless of BMD changes.
• Weak: For women aged 65 and older who have osteopenia and are at high fracture risk, consider patient preference, fracture-risk profile, benefits, harms, and medication cost.
• Weak: In men with clinically recognized osteoporosis, clinicians should offer bisphosphonate therapy to reduce vertebral fracture risk; evidence is lacking on BMD monitoring in men.

Bisphosphonates are the most commonly used agents for osteoporosis.^28,57

Nonresponse

Patients generally experience non-response for 1 of 3 reasons: (1) nonadherence, (2) inability to tolerate bisphosphonates, or (3) poor absorption or unidentified underlying medical conditions that are increasing bone turnover.^58-60 Lack of response is defined as 2 or more incident fragility fractures or lack of bone turnover markers response and a significant decrease in BMD according to the International Osteoporosis Foundation.⁵⁹ Experts indicate that between 30% and 53% of patients fail to respond for one of these reasons,^60,61 and patients need to take the medication for at least 1 year to assess its effectiveness. After 3 to 5 years of therapy, clinicians need to conduct a comprehensive patient assessment to determine individualized risk for fracture, and discontinue treatment if appropriate.^44,62

Nonadhrence and inability to tolerate bisphosphonates are closely related. Adverse effects certainly contribute to nonadherence, and the inconvenience of taking medications, absence

of symptoms for underlying disease, comorbid conditions, age, and socioeconomic status do, too. For these reasons, it’s crucial to assess patients carefully and engage them in very pointed discussion of risks and benefits of receiving or forgoing treatment and the need for adherence. Acknowledging that nonadherence to therapy usually occurs early (after 6 to 7 months), the treatment team can increase monitoring and discussion at that time for strict adherence.⁶³ Regular contact with a health care provider professional after initiating osteoporosis treatment is one of few interventions shown to improve adherence.^64,65 If the drug or dosage form is a problem, switching to an alternative drug or dosage form can solve this medication-related problem. Pharmacists could consider programming an alert to schedule counseling around 6 months after treatment initiation. 

Researchers are attempting to determine why some patients who are adherent do not respond. When patients do not respond, clinicians need to look for secondary causes of bone loss and new medications or diseases that can cause bone loss. Researchers have made progress in identifying problem alleles. This indicates that in the future, clinicians may have better tools to predict which people will respond, although those who will not respond are harder to identify with current science.⁶²

Pharmacist Interventions

The American Pharmacists Association has included osteoporosis as a “core” chronic condition that can benefit from medication therapy management services.⁶⁶ Good continuing education can address bone health and help pharmacists live up to their potential as patient educators and advocates for effective treatment. Two studies have demonstrated that pharmacists can increase initiation of medications for osteoporosis.^55,67 The first, which enrolled patients on glucocorticoids, showed that pharmacists were particularly effective in persuading older adults and men to start treatment.⁵⁵ The second addressed postmenopausal women, and showed that pharmacist intervention for osteoporosis doubled the likelihood of medication uptake.

Table 5 lists pharmacists’ most important responsibilities for patients being treated for osteoporosis. Motivational interviewing helps patients understand why they need to start treatment. Some statements and questions that pharmacists should be prepared to communicate include the following^68,69:

• Expressing empathy: “I know that it can be difficult to take medication when it may make you feel bad for a few hours.”
• Developing discrepancy: “Can you tell me why you think it’s important to remain on your treatment? What might happen if you stop it?”
• Rolling with resistance: “I hear what you are saying about side effects. What do you think about [changing the time you take the medication/switching to a new drug].
• Reflective listening and supporting self-efficacy: “I can tell that you are weighing risks and benefits carefully. How can I help you make your decision?”
• Asking-providing-asking: “Please tell me what you know about osteoporosis…OK, may I tell you a few thing I think you’d like to know?” Finish with, “What are your thoughts on what I just told you?”
• Affirming and summarizing: Here, reiterate patients’ statements, especially those that suggest a desire for change and reiterate your support to help with the change.

Pharmacists and other health care providers can employ a tool developed by the World Health Organization (WHO) to help evaluate potential future risk for a fracture. The Fracture Risk Assessment (FRAX) weighs patient-specific factors including age, sex, weight, height, medication use, history of parental fracture, and lifestyle factors (smoking status and alcohol use) to determine the 10-year probability of a major osteoporotic-related fracture and of a hip fracture. This tool is most effective if the clinician can include a femoral neck BMD result, but it does not require it to evaluate the probability of a future fracture. The FRAX is available online (https://www.sheffield.ac.uk/FRAX/) at no charge. Two large U.S. cohorts have validated its use in the U.S. FRAX Results cannot be used to diagnose osteopenia or osteoporosis; however, it can guide decisions for BMD screening.

Conclusion

In care of people who have osteoporosis, backsliding has become the order of the day. The statistics underscore the problem’s magnitude. Pharmacists can contribute significantly to increase preventive measures, identify patients who need treatment, and work with patients to ensure they are adherent to treatment and can manage adverse effects.

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