Regaining Ground in Osteoporosis: Pharmacists

Leading the Charge

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 startling14,15:

 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.

Table 1. Risk Factors for Osteoporosis2,20-25

Non-modifiable risk factors
Risk Factor Notes
Age older than 50 In individuals older than 50, fracture risk doubles every 7 to 8 years
years
Ethnic background Caucasian (white) at highest risk
Family history of Family history of spine or hip fractures
osteoporosis
Female sex and ■ Women’s risk for osteoporosis is greater than men’s because of estrogen’s role in bone health.
post-menopause ■ Accelerated bone loss begins 1 year before final menses and lasts for approximately 3 years
■ Following complete menopause, bone loss decreases by 1% to 1.5% annually.
History of Past fracture without major trauma (other than fingers, toes, skull) after age 50 years
fractures
Modifiable risk factors
Risk Factor Notes
Calcium and · Women aged 50 or younger and men age 70 or younger should consume 1,000 mg of calcium daily
vitamin D intake · Women older than 50 years and men older than 70 years consume 1,200 mg of calcium per day.
· Dietary consumption is preferred, but the recommended quantities include both dietary and supplement
intake.
· Calcium-rich foods (~200 mg or more) include dairy products (e.g., low-fat milk, yogurt, cheese),
sardines, tofu, fortified foods (e.g., orange juice), frozen collard greens, broccoli rabe, and canned baked
beans.
· Women and men younger than 50 should consume 400-800 IU of vitamin D per day
· Women and men aged 50 years or older should consume 800-1,000 IU of vitamin D per day.
Medical conditions· Cancer (e.g., breast, prostate, leukemias, lymphomas)
· Chronic kidney disease
· Endocrine disorders including hyperparathyroidism, adrenal insufficiency, autoimmune diseases (e.g.,
rheumatoid arthritis, lupus)
· Gastrointestinal disorders (e.g., bariatric surgery, celiac disease)
· Human immunodeficiency virus
· Neurological disorders (e.g., stroke, multiple sclerosis)
Medications · Aromatase inhibitors (letrozole, anastrozole) inhibit androgen conversion to estrogens; withdrawal
results in only a partial recovery of BMD
· Androgen deprivation therapy (bicalutamide, leuprorelin) decreases testosterone and estradiol serum
levels
· Antiepileptic drugs increase vitamin D metabolism and inhibit osteoblast formation; risk depends on
treatment duration
· Oral glucocorticoids, especially when used for more than 3 months in doses > 2.5 mg/day of
prednisone or equivalent; these drugs impair osteoblast function, causing rapid decline in BMD within 3
to 6 months
· PPIs inhibit gastric acid production and secretion, and can impair calcium absorption and increase the
likelihood of fracture. Risk depends on treatment duration and dose; highest risk is use for >1 year or at a
high dose. PPI withdrawal for >1 year reverses fracture risk
· Thiazolidinediones. Postmenopausal women taking pioglitazone or rosiglitazone have a 4-fold increase
in fracture risk.
Lifestyle choices · Low body weight (< 57.5 kg [127 lbs]) and/or low body mass index (< 21 kg/m2) increases risk for low
BMD and subsequent fractures.
· Tobacco use increases risk by impairing calcium absorption and suppressing estrogen levels,
· In women, consuming >2 alcohol-containing drinks (one drink equals 12 ounces of beer, 4 ounces of
wine, or 1 ounce of liquor) daily increases risk.
Physical activity Weight bearing exercises, such as walking, aerobics, and resistance exercise, have a positive impact on
bone mineral density
BMD = bone mineral density; IU = international units; PPI = proton pump inhibitor

*Consult with the American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis for guidance on
assessment, prevention, and treatment of this specific form of osteoporosis
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.

Table 2. Guideline Recommendations for Bone Mineral Density Screening and Initiation of Treatment28-35
Guideline (most recent Screening Initiation of Treatment
update)
American Association of All women ≥ 65 years old Patients with history of hip or spine fracture(s)
Clinical Endocrinologists and
American College of Younger post-menopausal women Patients with T-score ≤ -2.5 in the spine,
Endocrinology (AACE/ACE) · With prior fracture(s) (other than fingers, femoral neck, total hip, or 33% radius
toes, skull) without major trauma
2020 · Starting or taking long-term glucocorticoid Patients with T-score between -1.0 and -
therapy 2.5 and a FRAX probability for major
· With radiographic osteopenia osteoporotic fracture ≥ 20% OR hip fracture
· With clinical risk factors (see guideline for probability ≥ 3%
listed risk factors)
American College of All women ≥ 65 years old Women with a T-sore of < -2.5
Obstetricians and
Gynecologists (ACOG) Post-menopausal women < 65 years old who Women with T-score between -1.0 and -
are at risk of a fracture (see guideline for 2.5 and a FRAX probability for major
(2012) listed risk factors) osteoporotic fracture ≥ 20% OR hip fracture
probability ≥ 3%
Women with a FRAX probability for major
osteoporotic fracture ≥ 9.3% Women who have had a low-trauma fracture
American College of Assess clinical fracture risk within 6 months See guideline for treatment algorithms for
Rheumatology (ACR) of the start of long-term glucocorticoid patients taking glucocorticoid therapy
therapy and reassess every 12 months
(2017) (guideline has specific details for DXA
following risk assessment)
National Osteoporosis Women ≥ 65 years old All patients with hip or spine fracture (clinical
Foundation (NOF) or asymptomatic)
Men ≥ 70 years old
(2015) All patients with DXA T-score ≤ -2.5 at
Post-menopausal women < 65 years old with femoral neck, total hip, or lumbar spine
risk factors
Post-menopausal women & men ≥ 50 years old
Men between 50 and 69 years old with risk with osteopenia at femoral neck, total hip, or
factors lumbar spine and 10-year hip fracture
probability ≥ 3% OR 10-year major
Post-menopausal women and men > 50 years osteoporotic-related fracture probability ≥ 20%
old with an adult age fracture(s) (based on FRAX)
North American Menopause All women > 65 years old, regardless of All post-menopausal women who have had an
Society (NAMS) clinical risk factors osteoporotic vertebral or hip fracture

(2010) Post-menopausal women with medical causes All post-menopausal women with T-score ≤ -
of bone loss (e.g., steroid use or 2.5 at lumbar spine, femoral neck, or total hip
hyperparathyroidism), regardless of age region

Post-menopausal women with a fragility All postmenopausal women with T-score

fracture between -1.0 and -2.5 and a FRAX major
osteoporotic fracture probability ≥ 20% OR hip
Post-menopausal women > 50 years old with fracture probability ≥ 3%
1 or more risk factors (see guideline for listed
risk factors)
The Endocrine Society All men ≥ 70 years old Postmenopausal women at high risk of
fractures, especially those who have had a
(2020) Men 50–69 years old with additional risk recent fracture
factors (see guideline for listed risk factors)
Men Men who have had a hip or vertebral fracture
without major trauma
(2012)
Men with T-score ≤ -2.5 at the spine, femoral
neck, or total hip
 Men with T-score between -1.0 and -2.5 at the
spine, femoral neck, or total hip and a FRAX
any fracture probability ≥ 20% OR hip fracture
probability ≥ 3%

Men receiving long-term glucocorticoid

U.S. Preventive Services
Task Force (USPSTF)
(2018)
therapy (prednisone or equivalent > 7.5 mg/d)
All women ≥ 65 years old Not Applicable
Women < 65 years old with fracture
risk > that of a 65-year-old white woman who
has no additional risk factors

Insufficient evidence to recommend screening

in men
Abbreviations: DXA, dual energy X-ray absorptiometry; FRAX, Fracture Risk Algorithm
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).

Table 3. A Comparison of Calcium Carbonate and Calcium Citrate39

Calcium carbonate Calcium citrate
Elemental calcium 40% 21%
Administration Take with food Take any time
directions
Dose that promotes <500 mg <500 mg
absorption
Divide doses > 500 mg Divide doses > 500 mg
Absorption pH-dependent pH-independent (preferred in older adults, those taking PPIs, or those with
achlorhydria, inflammatory bowel disease, or absorption disorders)
Cost Inexpensive More expensive
Potential side effects Gas, bloating, Gas, bloating, constipation (less likely)
constipation (more
likely)
Drug interactions PPIs (calcium carbonate only) , bisphosphonates, levothyroxine, tetracyclines, fluoroquinolones,
phenytoin, and iron
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

Table 4. Summary of Available Bisphosponates46-49

BisphosphonateRoute Dose and Administration Notes
Alendronate PO* · 10 mg PO daily or 70 mg PO once weekly
· Available in an effervescent tablet
Ibandronate PO* or · 150 mg PO once monthly
IV** · A health care provider must administer the 3 mg IV formulation over 15-30 seconds every 3
months
Risedronate PO* · Osteoporosis treatment in postmenopausal women: 5 mg immediate release daily, 35 mg once a
week, 75 mg taken on two consecutive days each month, or 150 mg once a month
· Osteoporosis prevention in postmenopausal women: 5 mg daily, or 35 mg once a week
 · Men with Osteoporosis: 35 mg once a week (2.3)
· Treatment and prevention of glucocorticoid-induced osteoporosis: 5 mg daily
· Paget’s disease: 30 mg daily for 2 months
Zoledronic acid IV** · 5 mg IV infusion given over at least 15 minutes once yearly at an infusion center
*Do not use if CrCl <35 mL/min (<30 for risedronate, ibandronate), or if patient has hypocalcemia, esophageal stricture, or achalasia

**Do not use if CrCl <30-35 mL/min or evidence of acute kidney injury; do not use in patients at risk for acute kidney injury or with hypocalcemia
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 [achlorhydria, IBD…].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 following68,69:

 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.

Table 5. Pharmacists’ Responsibilities for Patients with Osteoporosis

Responsibility Key Points
Basic and continuing patient ■ Discuss the disease and the need for lengthy treatment
education ■ Recommend effective reminders, especially if patients are on once-weekly oral
medications
Promotion of positive lifestyle ■ Help patients determine the daily recommended quantities of calcium and vitamin D;
changes and improved calcium and assess dietary intake and suggest ways to increase consumption via diet and/or
vitamin D uptake supplementation
■ Inquire about current activity levels and suggest appropriate modifications and/or
 increase
Medication-adherence monitoring ■ Consider dosage forms and dosing schedules and their effect on adherence
■ Counsel on ways to manage side effects or barriers
■ Suggest reminder techniques
Consultation to help patients avoid ■ Ask proactively about potential adverse effects
medication adverse events
Referral to the prescriber ■ Identify bisphosphonate drug holiday opportunities
■ Contact prescriber when a switch from oral to intravenous administration seems
prudent
Assistance with cost barriers ■ Suggest older adults look for a Medicare Part D plan that covers medications for
osteoporosis
■ The Patient Access Network (PAN) Foundation’s Postmenopausal Osteoporosis
assistance program helps federally and commercially insured people with the out-of-
pocket costs for prescribed medications.
panfoundation.org/patients/assistance-programs or 1-866-316-7263
■ Refer underinsured patients to the HealthWell Foundation; it assists with copayments,
premiums, deductibles and out-of-pocket expenses. healthwellfoundation.org or 1-800-
675-8416.
■ NeedyMeds (www.NeedyMeds.com) searches for available help for individual
medications, Medicare state programs, drug discount card and more.
Identification of “red flags” ■ Watch for significant potential drug interactions and indications that nonadherence is a
problem (e.g., late refills)
■ Assess for likelihood of falls and recommend deprescribing any medications that may
increase risk of falls if possible
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.

1. Reginster JY. Antifracture efficacy of currently available therapies for postmenopausal

osteoporosis. Drugs. 2011;71(1):65–78.
2. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in
clinical practice. Mayo Clin Proc. 2008;83(9):1032-1045.
3. FOSAMAX (alendronate). Prescribing information. Merck; 2019.
4. BONIVA (ibandronate). Prescribing information. Genentech;2019.
5. ACTONEL (risedronate). Prescribing information. Procter & Gamble Pharmaceuticals,
Inc.;2009.
6. ZOMETA (zoledrenic acid). Prescribing information. Novartis Pharmaceuticals
Corporation;2016.
7. PROLIA (denosumab). Prescribing information. Genentech;2020.
8. EVISTA (raloxifene). Prescribing information. Eli Lilly & Co.:2018.
9. FORTEO (teriparatide). Prescribing information. Eli Lilly & Co.:2018.
10. TYMLOS (abaloparatide). Prescribing information. Radius Health, Inc.; 2020
11. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid
treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture
Trial (PFT) [published correction appears in J Bone Miner Res. 2012 Dec;27(12):2612]. J
Bone Miner Res. 2012;27(2):243-254.
12. Murphy-Menezes M. Role of the pharmacist in medication therapy management services
in patients with osteoporosis. Clin Ther. 2015;37(7):1573-1586.
13. Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in
postmenopausal women: an Endocrine Society clinical practice guideline. J Clin
Endocrinol Metab. 2019;104(5):1595-1622.
14. Qaseem A, Forciea MA, McLean RM, Denberg TD. Clinical Guidelines Committee of
the American College of Physicians. Treatment of Low Bone Density or Osteoporosis to
Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the
American College of Physicians.. [published correction appears in Ann Intern Med. 2017
Sep 19;167(6):448]. Ann Intern Med. 2017;166(11):818-839.
15. Vasikaran S, Eastell R, Bruyere O, et al. Markers of bone turnover for the prediction of
fracture risk and monitoring of osteoporosis treatment: a need for international reference
standards. Osteoporos Int. 2001;22:391-420.
16. Hannon RA, Blumsohn A, Naylor KE, Eastell R. Response of biochemical markers of
bone turnover to hormone replacement therapy: impact of biological variability. J Bone
Miner Res. 1998;13:1124-1133.
17. Naylor KE, Jacques RM, Paggiosi M, et al. Response of bone turnover markers to three
oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO
study. Osteoporos Int. 2016;27(1):21-31..
18. Diez-Perez A, Adachi JD, Agnusdei D, et al. Treatment failure in
osteoporosis. Osteoporosis Int. 2012;23(12):2769–74.
19. Marozik P, Alekna V, Rudenko E, et al. Bone metabolism genes variation and response
to bisphosphonate treatment in women with postmenopausal osteoporosis. PLoS
One. 2019;14(8):e0221511.
20. Tosteson ANA, Grove MR, Hammond CS, et al. Early discontinuation of treatment for
osteoporosis. Am J Med. 2003;115:209-216.
21. Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and persistence
with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled
trial. J Clin Endocrinol Metab. 2004;89:1117-1123.
22. Briot K, Ravaud P, Dargent-Molina P, et al.. Persistence with teriparatide in postmeno-
pausal osteoporosis; impact of a patient education and follow-up program: the French
experience. Osteoporos Int. 2009;20:625-630.
23. Burns A. Medication therapy management in pharmacy practice: core elements of an
MTM service model. American Pharmacists Association Accessed at
https://www.sciencedirect.com/science/article/abs/pii/S1544319115312164,March 10,
2021.
24. Bowers BL, Drew AM, Verry C. Impact of pharmacist-physician collaboration on
osteoporosis treatment rates. Ann Pharmacother. 2018;52(9):876-883.
25. Shannon R, Hillsdon M. Motivational interviewing and musculoskeletal
care. Musculoskeletal Care. 2007; 5(4):206-215.
26. McCarley P. Patient empowerment and motivational interviewing: engaging patients to
self-manage their own care. Nephrol Nurs J. 2009;36(4):409-413.