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MANAGEMENT OF OSTEOPOROSIS: SUPPORTING CONTINUITY OF CARE

Module 1: Osteoporosis Medications

and Treatment Guidelines

CCCEP Information

File no.: #1057-2020-3111-I-P

Expiry: November 2, 2021

Module 1: Osteoporosis Medications and Treatment Guidelines

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Faculty

Tom Smiley, BScPhm, PharmD, CTE Nese Yuksel, BScPharm, PharmD, FCSHP, NCMP

Reviewers

Dragana Sunjic, BScPhm Karen Riley, BScPhm, PharmD, BCPS, BCGP, BCACP, CDE

Disclosures

One of the faculty members is a member of advisory boards for commercial entities other than this sponsor.

The second faculty member and both expert reviewers have no conflicts of interest to declare.

An educational service for Canadian pharmacists brought to you by Amgen Canada.

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Introduction

This program has been designed to help reinforce your knowledge about osteoporosis management and treatment options. This module reviews the pathophysiology of osteoporosis and the burdens and care gaps associated with the disease and will share real-life patient story of a woman living with osteoporosis provides a different perspective for learners. The currently available treatment options are also explored in depth as well as key practice guidelines to support medication recommendations or prescribing of non-pharmacologic and pharmacologic therapies. In many cases one must consider provincial drug plan accessibility of various treatment options when prescribing. Therefore, a detailed listing of provincial drug plan eligibility for payment is reviewed for each province.

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Learning Objectives

Upon completion of this module, pharmacists will be better able to:

1. Describe osteoporosis and discuss the burden of disease.

2. Review the dose, administration, indications, warnings and precautions for all available medications for osteoporosis.

3. Compare access to the different osteoporosis medications across the country.

4. Review osteoporosis treatment guideline recommendations, including those specific to long term care.

Defining Osteoporosis

Osteoporosis (OP) has been defined as a systemic skeletal disease characterized by a reduction in bone mass and qualitative skeletal changes associated with microarchitectural deterioration of bone tissue that results in an increased risk for bone fragility and fracture.1,2 Osteoporosis can be defined as primary osteoporosis, due to age-related changes or loss of estrogen in menopause, or as secondary osteoporosis that is caused by medical conditions and/or medications.

For study, epidemiological and diagnostic purposes, the World Health Organization (WHO) has defined OP as a bone mineral density (BMD) of 2.5 or more standard deviations below that of the peak bone mass of healthy young adults (i.e., T-score ≤ 2.5) as measured by dual energy x-ray absorptiometry (DEXA).3,4 Individuals with a BMD T-score between -1 and -2.5 are said to have osteopenia (low bone mass).3

However, BMD is only one of a number of risk factors for fragility fracture and cannot be relied upon for diagnosis of OP.3 In fact, most fragility fractures occur in individuals with a T-score that is higher than -2.5 and more than 10% of osteoporosis-related fractures occur in people with normal BMD.5

For that reason, the World Health Organization Fracture Risk Assessment (FRAX) tool or the updated tool of the Canadian Association of Radiologists and Osteoporosis Canada (CAROC) are

used to identify people at high 10-year absolute risk for osteoporotic fracture as they take other risk factors into

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consideration in addition to BMD.6 These tools are discussed in detail in Module 2. Risk factors that identify individuals that should be referred for BMD testing via DEXA are listed in Table 1.

Did You Know?

One in three women and one in five men will suffer from an osteoporosis-related fracture in their lifetime .7

Pathophysiology of Osteoporosis

The fragility of bones associated with OP is a result of reduced bone mass and bone quality (i.e., negative changes in bone architecture).8 The process by which old bone is resorbed and new bone is laid down is known as the “remodelling cycle”. As a result, renewal of the skeleton occurs approximately every 10 years.3 At a younger age, the amount of bone laid down is similar to the amount resorbed.

However, with aging, different genetic and environmental factors result in varying levels of reduced bone formation and changes in bone microarchitecture.³ Risk factors for OP are listed in Table 1.

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Table 1: Osteoporosis Risk Factors 6

Personal characteristics

• Age > 50 years old

• Vertebral fractures

• Personal fragility fracture after the age of 40

• Family history (especially parental history of hip fracture)

• Race/ethnicity (Caucasian, East Asian)

• Early menopause (< 45 years)

• Low body weight or major weight loss Lifestyle factors

• Current smoking

• High alcohol intake (> 3 drinks per day)

• Low calcium intake

• Low vitamin D intake or deficiency

• Low physical activity

• High caffeine intake Hypogonadal states

• Women: early menopause (<45 years), premature ovarian insufficiency, previous amenorrhea (anorexia, athletic)

• Men: hypogonadism Endocrine disorders

• Hyperparathyroidism

• Hyperthyroidism

• Cushing’s syndrome

• Type 1 and 2 diabetes Rheumatologic disorders

• Rheumatoid arthritis

• Systemic lupus

Gastrointestinal disorders

• Celiac disease

• Inflammatory bowel disease

• Other malabsorption diseases Other diseases/disorders

• Chronic kidney diseases

• Chronic obstructive pulmonary disease

• HIV

• Malignancies (e.g., multiple myelomas, leukemia, lymphoma)

Medications associated with bone loss or fractures

• Glucocorticoids (> 3 months cumulative dose in past year at prednisone dose ≥ 7.5 mg or equivalent/day or greater)

• Anticonvulsants

• Aromatase inhibitors

• Antiandrogen therapy

• Excess thyroid replacement

• Anticoagulants (long-term heparin therapy)

• Chemotherapy

• Depo-medroxyprogesterone

• Gonadotropin-releasing hormone (GnRH) agonists

• Selective serotonin reuptake inhibitors

• Proton pump inhibitors

• Preformed retinol/vitamin A supplements > 10,000 IU

• Thiazolidinediones

• Antiretrovirals (tenofovir, certain protease inhibitors)

Reprinted/adapted by permission from Springer Nature and Copyright Clearance Center: Springer Nature, Patient Assessment in Clinical Pharmacy: Osteoporosis by Yuksel, N and Charrois TL. Copyright. January 1, 2019.

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Pathophysiology of Osteoporosis at a Molecular Level

An understanding of the pathophysiology of osteoporosis at a molecular level is necessary for the understanding of the mechanisms of action of treatment options. The remodeling units of bone are known as basic multicellular units (BMUs) and include osteoclasts which are responsible for bone resorption, osteoblasts which are responsible for bone formation and osteocytes which are older osteoblasts that are surrounded by bone.8

The most common time for “uncoupled remodelling” (i.e., bone resorption exceeds bone formation) is during menopause when estrogen deprivation occurs and shifts resorption rates to a higher set point.8 Advancing age in both women and men is also associated with a degree of remodelling imbalance which favours loss of bone tissue.9 The imbalance results in the disordered skeletal architecture which increases fracture risk.9 There are several additional reasons for uncoupled remodeling which include endogenous parathyroid hormone fluxes, cytokine stimulation, growth hormone surges, glucocorticoid excess, and changes in serum calcium/vitamin D.8

The interaction of osteocytes, osteoblasts and osteoclasts is very complex and affected by many external signals which result in release of a variety of cytokines such as IL-1, IL-6, IL-11, M-CSF, tumour necrosis factor (TNF), and TGF-beta.8 As a result, bone resorption activities increase. One of the most important pathways with respect to osteoblast-osteoclast interaction is the RANKL-Osteoprogenin relationship. RANKL binds to receptors on osteoclasts and initiates osteoclast activation. Osteoprogenin (OPG) is a soluble peptide that markedly inhibits bone resorption and osteoclast differentiation. It does this by acting as a decoy receptor for RANKL which is a surface peptide that is expressed on osteoblasts. RANKL is the target of a monoclonal antibody (denosumab).8

Sclerostin is a peptide secreted by osteocytes that inhibits bone formation by blocking a signalling pathway that known as Wnt that regulates cell growth and differentiation. Sclerostin is the target of a new monoclonal antibody (romosozumab).3,8

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The Burden of Osteoporosis

Osteoporosis Canada reports that over 80% of all fractures that occur after 50 years of age are caused by osteoporosis.11 Osteoporosis has been recognized as a “silent disease” until fragility fractures occur as a result of minimal or no trauma.10 In fact, eighty percent of the 200,000 Canadians that break a bone and 30,000 that suffer a hip fracture annually have osteoporosis.7 Following are some key statistics related to the burden of osteoporosis in Canada:11,12

• The most recent estimate for overall cost of osteoporosis in Canada (fiscal year 2010/11) was $4.6 billion. This estimate includes costs for acute care, physician visits, prescription drug costs, rehabilitation, complex continuing care, mobility devices, home care and long-term care (LTC) and wage losses.12

• Hip fracture is the type of fracture that is associated with greatest loss of quality of life and functional status.³ Approximately 15-25% of people who experience a hip fracture are admitted to nursing homes. This adds to wait times for nursing home beds and uses up orthopaedic resources which are already depleted. Hip fractures alone are expected to impact Canadian health care costs by $2.4 billion each year by 2041.11

The Impact of COVID-19

The impact of COVID-19 has negatively affected disease management of many diseases, including osteoporosis. In-person health professional and rehabilitation visits have been cancelled in many cases and medications have not been as accessible. Pharmacists should help support patients by ensuring that they are aware of options during these times.

Three medications that have strict injection administration schedules include:

Zoledronic acid

• Administered by infusion once per year13

• Since it remains in the system a longer period of time than the other medications it may be delayed for a short period if necessary.13

Denosumab

• Administered once every 6 months13

• Home (such as self-injection) or pharmacy injection may be discussed and implemented.13

Romosozumab

• Administered once a month13

• Home (such as self-injection) or pharmacy injection may be discussed and implemented.13

Note: Pharmacists and their staff should help facilitate communication with the health professional administering the drug in these circumstances.

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A Condition That is Often Overlooked Because patients and healthcare professionals often perceive osteoporosis as a disease that is not serious, it does not get the attention that it deserves. However, fractures caused by osteoporosis are more common than heart attack, stroke and breast cancer combined and often result in disability, loss of independence, and premature death.5,14

Despite the fact that fragility fractures cause reduced quality of life secondary to pain and suffering and severe disability and are responsible for high use of long-term care and rehabilitation resources, many care gaps exist in the management of osteoporosis.10 This is supported by data suggesting that over 80% of Canadians with fractures are never offered assessment and/or treatment for osteoporosis after the incident.11

A document published by the National Bone Health Alliance and the American Academy of Physicians suggest that there are four major care gaps associated with osteoporosis care. These include:10

1. Failure to follow guidelines for screening for osteoporosis. 2. Failure to treat patients who sustain a fragility fracture to prevent a future fracture. 3. Poor patient communication by health professionals to educate about risks and

consequences of osteoporosis and fractures. 4. Poor follow-up after prescribing osteoporosis medications which leads to poor adherence

and suboptimal patient outcomes.

Addressing the Care Gaps

In Canada and around the world it is widely recognized that methods for addressing care gaps in osteoporosis care are needed.15 As primary health care providers that are in contact with patients more than any other health care provider, pharmacists are in a unique position to address care gaps that include identification, assessment and treatment of patients at risk of fracture. All women and men age 50 years and older or those younger with secondary causes should be assessed for OP risk and those found to be at high risk referred appropriately. Providing recommendations for appropriate OP treatment is an important role for the pharmacist.

For patients taking OP medication, assessment of medication appropriateness through identification and management of drug interactions, medication contraindications, adverse reactions and long-term risks with medications is an important pharmacist activity in addition to adherence monitoring and support for patients experiencing adverse effects.

The identification of risk factors in patients, assessment of OP risk, recommendation of appropriate treatment and follow-up with patients is reviewed in detail in Module 2.

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Fracture Liaison Service

A fracture liaison service (FLS) is a model of care where people who have experienced a fracture are proactively identified in order that effective treatment for high-risk patients may be facilitated. In order to address this need, protocols for an FLS have been devised and utilized in many locations globally.15 Performance indicators for FLS include identification of patients (percentage of patient presented to setting that were enrolled in FLS), investigation (proportion of enlisted patients investigated to determine fracture risk within 3 months) and percentage of high-risk patients placed on first-line OP medication within 6 months.

A 2017 audit of Canadian settings (mostly hospitals) providing FLS found the initiative to be bridging the osteoporosis care gaps.16 Keep in mind that without FLS, less than 25% of patients with fragility fractures are diagnosed and/or treated for osteoporosis.16

Despite the potential for FLS to help close the gaps in osteoporosis care, only 47 FLS settings existed in Canada as of September 1, 2018. Healthcare professionals and institutions desiring more information about the Canadian FLS Network and how to join should click on the link.

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Osteoporosis Medications: How they work

Osteoporosis medications can be classified as either antiresorptive or anabolic.17 Antiresorptive drugs decrease osteoclast function to prevent resorption of bone. Anabolic drugs increase bone formation via various mechanisms.17,18 Antiresorptive medications include:18

• Bisphosphonates: Alendronate, risedronate, etidronate and zoledronic acid are bisphosphonates that bind to hydroxyapatite crystals in bone at sites of active bone remodelling, thereby slowing down bone resorption by inhibiting hydroxyapatite breakdown.19

• RANK ligand inhibitors: Denosumab is a biologic agent (monoclonal antibody) that binds to the receptor activator of nuclear factor kappa-B ligand (RANKL), thereby inhibiting its interaction with the RANK receptor on the surface of osteoclasts and osteoclast precursors.18 This serves to decrease the formation of osteoclasts as well as their function and survival, resulting in a significant reduction in bone resorption at both cortical and trabecular bone sites.18

• Hormone therapy: Estrogen is an important regulator of bone mass as demonstrated by the onset of osteoporosis in postmenopausal women with low estrogen levels.20 Although it is know that estrogen receptors are widely expressed on a variety of cells in bone and bone marrow, the exact cells responsible for the effects of estrogen on bone are still a matter of debate.20

• Selective estrogen receptor modulators: Raloxifene acts as an estrogen antagonist in breast and uterine tissue but has estrogen-like activity in bone and lipid metabolism in postmenopausal women.18

• Parathyroid hormone: Teriparatide consists of the 34 N-terminal amino acids of the parathyroid hormone. It regulates bone metabolism, renal tubular reabsorption of calcium and phosphate and intestinal calcium reabsorption, resulting in building of bone (anabolic activity).21

• Sclerostin inhibitor: Romosozumab is a humanized IgG2 monoclonal antibody with high affinity and specificity for sclerostin, a regulatory factor in bone metabolism that inhibits the bone building activity of osteoblasts.22 By inhibiting sclerostin, romosozumab has a dual effect on bone, increasing bone formation (anabolic activity) and decreasing bone resorption.

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Bisphosphonates Acronyms: PM = postmenopausal, OP = osteoporosis DR = delayed-release BMD = bone mineral density

Alendronate18,23

Available dosage forms and strengths

5 mg, 10 mg, 70 mg tablet 70 mg + vitamin D 2800 units or 5600 units tablet

Dosage and administration Dosage (treatment) – 70 mg po weekly (most common dose), 10 mg po daily

*As poorly absorbed, should be taken on empty stomach, at least 30 minutes (some clinicians say 60 minutes) before the first food or drink of the day or any other medications, with a full glass of water. Patient should be informed to not lie down for 30 minutes after taking due to risk of esophageal ulceration.

Contraindications Patients with abnormalities of the esophagus and inability to sit or stand for 30 minutes. Hypocalcemia Renal insufficiency with creatinine clearance < 35 mL/min Pregnancy and breastfeeding

Adverse effects Usually minimal: GI symptoms (dyspepsia, abdominal discomfort), musculoskeletal pain, diarrhea or constipation

Hypocalcemia, hypophosphatemia

Rare adverse effects Esophagitis, esophageal ulcers (rare if used properly)

Osteonecrosis of the jaw (ONJ), atypical femur fracture (AFF)

Warnings and precautions Avoid use in patients with creatinine clearance < 35 mL/min

See “Warnings and Precautions for bisphosphonates” on main bisphosphonates slide.

Important Note: Warnings and precautions for bisphosphonates (alendronate, risedronate, zoledronic acid), denosumab and romosozumab:18,22,27 Osteonecrosis of the jaw (ONJ) refers to exposure of the bone of the upper and/or lower jaw that does not heal after six weeks which most often occurs after dental work that is associated with local trauma to the oral cavity such as tooth extraction or dental implants. It is a rare occurrence with the long term use of some bisphosphonates (alendronate, risedronate, zoledronic acid), denosumab and romosozumab. However, patients should be advised to complete elective dental work whenever possible before therapy. They should also inform their dentist that they are taking this medication before having any dental work.

Atypical femoral fractures (AFF) usually presenting as spontaneous fracture in the subtrochanteric region of the femur have been identified as a rare occurrence after long term use (>5 – 7 years) of bisphosphonate users, and denosumab . If any signs of AFF, such as sudden onset of thigh, hip or groin pain are identified, patients should be referred for further assessment.

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Risedronate18,24

Available dosage forms and strengths

5 mg, 35 mg, 150 mg tablet 35 35 mg delayed-release (DR) tablet

Dosage and administration Dosage 35 mg po weekly (most common dose), 150 mg po monthly, 5 mg daily

See alendronate chart (*) for administration instructions of tablets.

35 mg DR tablets should be taken in the morning with breakfast.

Contraindications Patients with abnormalities of the esophagus and inability to sit or stand for 30 minutes. Hypocalcemia Pregnancy and breastfeeding

Adverse effects Usually minimal: GI symptoms (dyspepsia, abdominal discomfort), musculoskeletal pain, diarrhea or constipation

Hypocalcemia, hypophosphatemia

Rare adverse effects Esophagitis, esophageal ulcers (rare if used properly)

Osteonecrosis of the jaw (ONJ), atypical femur fracture (AFF)

Warnings and precautions Avoid use in patients with creatinine clearance < 30 mL/min

See “Warnings and Precautions for bisphosphonates” on main bisphosphonates slide.

Etidronate/Calcium18,25

Available dosage forms and strengths

Etidronate 400 mg tablets and calcium (as carbonate) 500 mg tablets in convenience pack

Dosage and administration Dose: Etidronate 400 mg tablet once daily for 14 days po then calcium 500 mg (as carbonate) on days 15 to 90 (take calcium with or after meals and separate administration with ciprofloxacin, iron, levothyroxine and tetracycline by 2 hours).

Etidronate should be taken on empty stomach with a full glass of water.

Contraindications Patients with osteomalacia (appropriate treatment should be initiated before prescribing etidronate)

Adverse effects Usually minimal: GI symptoms (dyspepsia, abdominal discomfort), musculoskeletal pain, diarrhea or constipation

Hypocalcemia, hypophosphatemia

Rare adverse effects ONJ, AFF: See +”Warnings and precautions for bisphosphonates” on main bisphosphonates slide.

Warnings and precautions Patients with impaired renal function or with a history of kidney stone. See +”Warnings and Precautions for bisphosphonates” on main bisphosphonates

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slide.

Zoledronic Acid18,26

Available dosage forms and strengths

5 mg/100 mL ready-to-use infusion

Dosage and administration 5 mg once yearly intravenously, infused over 15-30 minutes

Contraindications Severe renal impairment in patients with creatinine clearance < 35 mL/min and in those with evidence of acute renal impairment

Non-corrected hypocalcemia at time of infusion

Pregnancy and nursing mothers

Adverse effects Infusion site reactions: Acute-phase reaction (fever and lymphopenia, joint or muscle pain, skin reactions, ocular effects) 24-72 hours after infusion, lasting up to 3-4 days in 10-20% of patients.

Hypocalcemia, hypophosphatemia

Rare adverse effects ONJ, AFF: see +”Warnings and Precautions for bisphosphonates” on main bisphosphonates slide.

Acute renal failure

Atrial fibrillation

Warnings and precautions See +”Warnings and Precautions for bisphosphonates” on main bisphosphonates slide.

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RANK Ligand Inhibitors

Denosumab18,27,28

Available dosage forms and strengths

60 mg subcutaneous (SC) injection, pre-filled syringe

Dosage and administration 60 mg SC once every six months (must be refrigerated)

Contraindications Hypocalcemia

Pregnancy and breastfeeding

Adverse effects Joint and muscle pain, rash/eczema, increased risk of infection (i.e., cellulitis), hypocalcemia in patients with renal impairment (ensure adequate calcium and vitamin D intake for all patients)

Rare adverse effects ONJ, AFF: see +“Warnings and Precautions for bisphosphonates” on main bisphosphonates slide

Warnings and precautions Increased risk of vertebral fractures upon continuation of denosumab. Consider another osteoporosis medication if denosumab is discontinued.

Note: No dosage adjustment is required for renal impairment. Greater risk of hypocalcemia in patients with renal impairment. Monitor calcium and signs of hypocalcemia.

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Hormone Therapy

Estrogen and Progesterone30-34

Available dosage forms and strengths

Conjugated estrogens oral tablets 0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg

17β-estradiol oral tablets 0.5 mg, 1 mg, 2 mg

Estradiol hemihydrate topical 50 mcg, 75 mcg, 100 mcg

Estradiol-17β transdermal 25 mcg, 37.5 mcg, 50 mcg,75 mcg, 100 mcg

Estradiol gel 0.06%, 0.1%

Dosage and administration - 0.625 mg of conjugated estrogen or equivalent

Contraindications Estrogens and estrogen/progestin combinations are contraindicated in the following circumstances:

• Active or past history of confirmed venous thromboembolism

• Known, suspected, or past history of breast cancer

• Undiagnosed abnormal vaginal bleeding

• Active or past history of cardiovascular disease (e.g., myocardial infarction, coronary heart disease)

• Active or past history of stroke

• Partial or complete loss of vision (or diplopia) due to ophthalmic vascular disease

• Active liver disease

Adverse effects Nausea, breast tenderness, fluid retention, bloating, headache, mood changes (irritability, depression), fatigue, micronized progesterone can cause drowsiness

Warnings and precautions Estrogens with or without progestins should be used at the lowest effective dose and for the shortest time needed for symptom management.

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Selective Estrogen Receptor Modulator

Raloxifene18,29

Available dosage forms and strengths

60 mg tablets

Dosage and administration 60 mg daily po at any time of day (No indication for men)

Should not be initiated until menopause is established as drug may aggravate hot flashes.

Contraindications Active or past history of venous thromboembolic events

Women of childbearing age, men

Adverse effects Leg cramps, hot flashes (especially in younger PM women).

Warnings and precautions Venous thromboembolism risk similar to estrogen.

Parathyroid Hormone

Teriparatide18,21,35

Available dosage forms and strengths

250 mcg/mL in 3 mL prefilled syringe

250 mcg/mL in 2.4 mL prefilled syringe

Dosage and administration 20 mcg once a day administered by subcutaneous injection into the thigh or abdominal wall.

Patients should be in a supine or sitting position during administration due to risk of orthostatic hypotension.

Contraindications Hypercalcemia.

CrCl <30 mL/min

Metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism and Paget's disease of the bone).

Bone metastases or a history of skeletal malignancies.

Pregnancy and nursing mothers

Adverse effects Nausea, dizziness, leg cramps, hypercalcemia, injection site erythema.

Rare adverse effects Hypercalcemia. Theoretical risk of osteosarcoma (seen in rats); clinical significance in humans is unknown.

Warnings and precautions Maximum lifetime exposure to teriparatide for an individual patient is 24 months.

Should be administered under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur.

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Sclerostin Inhibitor

Romosozumab22,36-39

Available dosage forms and strengths

Single-use prefilled syringe containing 105 mg romosozumab in 1.17 mL solution for injection.

Packages of two prefilled syringes.

Dosage and administration Dose: 210 mg (2 prefilled syringes) SC once per month in abdomen, thigh or upper arm.

Contraindications Hypocalcemia History of myocardial infarction or stroke Pregnancy

Adverse effects Joint pain, muscle spasm, headache, swelling of extremities, injection site reactions, nasopharyngitis, occurrences of hypocalcemia (uncommon <1%)

Rare adverse effects May increase the risk of cardiovascular events (myocardial infarction, stroke), (occurred in 0.1% to 1% of patients – occurred more frequently than with alendronate; however, studies comparing to placebo did not see an increase), hypersensitivity-angioedema, erythema multiforme.

Warnings and precautions Consideration must be given as to whether the benefits outweigh the risks in patients with cardiovascular or cerebrovascular disease or associated risk factors (also see contraindications).

Note: No dosage adjustment needed for renal impairment. Greater risk of hypocalcemia in patients with renal impairment. Monitor calcium and signs of hypocalcemia. Supplement adequately with calcium and vitamin D.

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Monitoring of Osteoporosis Therapies

Adverse effects as listed in each of the drug charts should be monitored. Signs and symptoms of hypocalcemia associated with use of denosumab and romosozumab. Monitor calcium level prior to initial dose and repeat in 2 weeks after initial dose.27 Symptoms of hypercalcemia (e.g., nausea, vomiting, lethargy, muscle weakness) should be monitored when using teriparatide and calcium levels should be monitored.21 BMD is normally monitored every 1 to 3 years (average every 2 years).9 In some instances biochemical markers of bone turnover (e.g., alkaline phosphatase) may be used to monitor therapy (higher turnover rate means increase in bone resorption).18

Osteoporosis Treatment Guidelines - Pharmacotherapy

There are many different osteoporosis treatment guidelines available to help guide therapy. The most recent general Canadian guidelines for osteoporosis treatment in Canada were published in 2010 (new guidelines are expected in late 2020).40 Despite being dated, newer guidelines from around the world show mostly striking similarities with respect to who should receive medications to treat OP, the choice of first-line medications and lifestyle recommendations. The key messages from the Canadian guidelines and some caveats related to newer recommendations are presented in Tables 2 and 3 below.

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Table 2 : Summary of 2010 Osteoporosis Canada Guideline and current best practice recommendations for pharmacological treatment of osteoporosis41

OP should be treated with pharmacotherapy in the following circumstances: 10-year fracture risk > 20% (see Module 2) or prior fragility fracture of hip or spine or > 1 fragility fracture. For women and men at high risk for fractures requiring treatment of osteoporosis, alendronate, risedronate, zoledronic acid and denosumab are first-line therapies for prevention of hip, nonvertebral and vertebral fractures in menopausal women with vasomotor symptoms. Other osteoporosis medications:

• Raloxifene can be used as first-line therapy for prevention of vertebral fractures. Hormone therapy can be used as first-line therapy for prevention of hip, nonvertebral and vertebral fractures in menopausal women with vasomotor symptoms.

• Etidronate can be considered for prevention of vertebral fractures for women intolerant of first-line therapies

• Teriparatide is indicated for women with severe post-menopausal OP and men with severe OP that have not responded to other therapies

• Romosozumab is indicated for the treatment of OP in PM women at high risk for fracture. Due to cost, teriparatide and romosozumab are most often used for patients who are not responding to other therapies. Summary of 2010 Osteoporosis Canada Guideline and current best practice recommendations for pharmacologic treatment of osteoporosis.41 Appropriate therapy for special groups: Glucocorticoid-induced osteoporosis (GIOP): Consider prevention of osteoporotic fractures for individuals over the age of 50 (or patients at high risk of fracture) who will be on long term glucocorticoid therapy (>3 months cumulative therapy during preceding year at a prednisone dose of > 7.5 mg daily or equivalent):

Considerations of both prevention and treatment of GIOP include: oral bisphosphonate (alendronate, risedronate) IV bisphosphonate, denosumab or teriparatide

* Women who are taking aromatase inhibitors and men who are undergoing androgen deprivation therapy should be assessed for fracture risk, and osteoporosis therapy to prevent fractures should be considered.

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Table 3: Guideline recommendations for non-pharmacological treatment of osteoporosis41

Calcium Daily intake of elemental calcium from all sources for individuals over age 50 should be 1200 mg.

Vitamin D For healthy adults at low risk of vitamin D deficiency routine supplementation with 400-1,000 IU vitamin D is recommended. For adults over age 50 at moderate risk of vitamin D deficiency, supplementation with 800-1,000 IU vitamin D daily is recommended. Higher daily doses of up to 2,000 IU may be required to achieve optimal vitamin D status.

Physical activity Exercise involving resistance training appropriate for the individual’s age and functional capacity and/or weight-bearing aerobic exercises are recommended for individuals at risk or with OP. Exercises to enhance core stability are recommended for individuals who have had vertebral fractures.

Prevention of falls Exercises that focus on balance, such as tai chi, or on balance and gait training should be considered for those at risk of falls. Patient should be educated to assess and address risks for falls.

Tobacco Promote tobacco cessation.

Alcohol Restrict alcohol intake to no more than 2 standard drinks per day.

Caffeine Restrict caffeine intake to less than 4 cups of coffee (<400 mg caffeine) per day.

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Summary of Effectiveness of OP Therapies for Fracture Prevention in PM Women

First-Line Therapies with Evidence for Fracture Prevention in Postmenopausal Women

Antiresorptive Therapy Anabolic Therapy

Dual Therapy

Alendronate Risedronate Zoledronic Acid

Denosumab Raloxifene HRT* (estrogen)

Teriparatide Romoso-zumab

Vertebral √ √ √ √ √ √ √ √

Hip √ √ √ √ X √ X √

Non-Vertebral

√ √ √ √ X √ √ √

*Used for women who also need HRT for treatment of vasomotor symptoms associated with menopause For men requiring treatment, alendronate, risedronate, and zoledronate can be used as first-line therapies for prevention of fractures. Nonvertebral fractures refer to a composite endpoint including hip, femur, pelvis, tibia, humerus, radius, and clavicle. Source: http://www.osteoporosis.ca/multimedia/pdf/Quick_Reference_Guide_October_2010.pdf

Key Osteoporosis Treatment Guidelines – Helpful Links 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary.

https://www.cmaj.ca/content/182/17/1864

AACE/ACE Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2020 https://www.aace.com/disease-state-resources/reproductive-and-gonad/clinical-practice-guidelines-recent-news-and-updates

Endocrine Society. Pharmacological management of osteoporosis in postmenopausal women: An Endocrine Society clinical practice guideline. (2019) https://academic.oup.com/jcem/article/104/5/1595/5418884

National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. (2014) https://link.springer.com/article/10.1007/s00198-014-2794-2

UK Clinical Guideline for the Prevention and Treatment of osteoporosis (2017) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397452/

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American College of Physicians. Treatment of low bone density or osteoporosis to prevent fracture in men and women: A clinical practice guideline update from the American College of Physicians (2017) https://www.ser.es/wp-content/uploads/2018/06/American-College-of-Physians-170607.pdf

Osteoporosis Canada. Recommendations for preventing fracture in long-term care. https://www.cmaj.ca/content/cmaj/187/15/1135.full.pdf

Access to Osteoporosis Medications

Access to OP medications varies across the provinces. The chart below shows available OP medications (except romosozumab) and status of access with respect to public health coverage. Keep in mind that employer third party coverage may provide access to the drug in circumstances where the public health benefits do not.

Full access, No restrictions

Special Authorization (SA)/Exceptional Access Criteria

Restricted reimbursement criteria

No access

PRODUCT BC AB SK MB ON QC NB NS PE NL

Alendronate

Alendronate/cholecalciferol (70mg/5600IU)

Risedronate

Zoledronic acid)

Etidronate/calcium carbonate

Denosumab

Raloxifene

Teriparatide

Note: At time of publication, romosozumab was not listed as a benefit on any provincial formularies

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Sources BC Pharmacare Formulary. https://pharmacareformularysearch.gov.bc.ca/faces/Search.xhtml

Alberta Blue Cross Formulary. https://idbl.ab.bluecross.ca/idbl/load.do

Saskatchewan Formulary. http://formulary.drugplan.health.gov.sk.ca/SearchFormulary

Manitoba Formulary. https://www.gov.mb.ca/health/mdbif/index.html

Ontario Drug Benefit Formulary. https://www.formulary.health.gov.on.ca/formulary/

RAMQ Formulary. https://www.ramq.gouv.qc.ca/en/media/8941

Newfoundland and Labrador Formulary. https://www.gov.nl.ca/hcs/prescription/idf/

New Brunswick Medicare Prescription Drug Plan Formulary. https://www2.gnb.ca/content/gnb/en/departments/health/MedicarePrescriptionDrugPlan/NBDrugPlan/ForHealthCareProfessionals/NewBrunswickDrugPlansFormulary.html

Nova Scotia Pharmacare Formulary. https://novascotia.ca/dhw/pharmacare/formulary.asp

PEI Pharmacare Formulary. https://www.princeedwardisland.ca/en/information/health-pei/pei-pharmacare-formulary.

Northwest Territories Formulary. https://www.nwticformulary.com/

NWT NIHB Benefits. https://www.sac-isc.gc.ca/DAM/DAM-ISC-SAC/DAM-HLTH/STAGING/texte-text/nihb_benefits-services_drugs_dbl-index_1573154657223_eng.pdf

Yukon Drug Formulary. https://yukon.ca/drug-formulary

Nunavut Drug Formulary. https://www.gov.nu.ca/health/information/ehb-full-coverage-plan

NIHB Formulary. https://www.sac-isc.gc.ca/DAM/DAM-ISC-SAC/DAM-HLTH/STAGING/texte-text/nihb_benefits-services_drugs_dbl-index_1573154657223_eng.pdf

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Long-Term Care Guidelines

The population of adults living in long-term care facilities have been shown to have a fracture rate that is 2 to 4 times that of adults living in the community.43 In addition, one-third of older adults experiencing a hip fracture in Canada are residents in long-term care.43 For this reason, the Scientific Advisory Council of Canada of Osteoporosis Canada developed guidelines that are unique for this patient population. A summary of the key messages is outlined below:43

1. Calcium and vitamin D: For residents at high risk of fractures who cannot meet the recommended dietary allowance for calcium and/or vitamin D, calcium supplements up to 500 mg and/or vitamin D 800-2,000 IU is strongly recommended. For residents not at high risk for fracture, calcium and vitamin D supplements should be considered based on calcium and vitamin D intake, resources, and preferences (e.g., calcium may cause adverse effects in some people).

2. For residents at high risk of fractures, alendronate (weekly) or risedronate (weekly or monthly) are recommended as first-line therapy based on effectiveness, need for only weekly or monthly dosing and low cost. For older individuals that cannot swallow or who have difficulty taking oral medications, denosumab and zoledronate are first-line alternatives.

3. Raloxifene is not recommended for use in residents at high risk of fractures due to risk of venous thromboembolism and musculoskeletal events such as arthralgia and myalgia that likely outweigh the probable reduction in fractures.

4. Etidronate is not recommended as use likely results in little to no reduction in fractures. 5. Hip protectors are recommended for residents who are mobile and at high risk of fractures. 6. Balance, strength and functional training exercises as appropriate for resident abilities are

recommended for all residents in order to prevent falls. 7. Multifactorial interventions (e.g., medication reviews, assessment of environmental

hazards, use of assistive devices, exercises, management of urinary incontinence and educational interventions directed to staff) should be individually tailored to reduce risk of falls and fractures.

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Key Learning Points

1. Osteoporosis is a systemic skeletal disease the causes loss of bone mass and negative effects on bone microarchitecture.

2. Osteoporosis is responsible for 80% of broken bones and 30,000 hip fractures in Canada each year.

3. Effects of risk factors on bone remodelling (reabsorption and laying down of bone) are responsible for the osteoporosis-related pathophysiology.

4. Classes of drugs which include bisphosphonates, RANK ligand inhibitors, selective estrogen receptor modifiers, hormone therapy, parathyroid hormone and sclerostin inhibitor address bone loss and architecture pathology via unique mechanisms of action.

5. Pharmacological treatment of osteoporosis must be individualized to each patient’s unique circumstances with attention to specific indications, dose, administration, warnings and precautions.

6. Access to public health coverage of osteoporosis medications varies across the provinces in Canada.

7. Non-pharmacological approaches to osteoporosis management include calcium and vitamin D supplementation, weight-bearing, muscle strengthening and balance exercises, additional falls prevention strategies, and strategies to reduce tobacco, alcohol and caffeine intake.

8. Many clinical practice guidelines for the management of osteoporosis exist in North America and around the world. Patient-focused and evidence-based approaches to treatment are generally very similar among the guidelines.

9. Long-term care guidelines which focus on the unique needs of higher risk residents in Canada are an important resource for Canadian health practitioners.

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References 1. Nuti R, Brandi ML, Checchia G, et al. Guidelines for the management of osteoporosis and fragility

fractures. Internal and Emerg Med. 2019;14: 85-102.

2. Qaseem A, Forciea M, McLean RM, et al. 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. Ann Intern Med. 2017 doi: 10.7326/M15-1361.

3. Compston JE, McCLung MR, Leslie WD. Osteoporosis. Lancet. 2019; 393: 364-376.

4. Brown P. Osteoporosis and fracture prevention in primary care, In: Connolly A, Britton A, editors. Women’s Health in Primary Care. Ch. 29;. Cambridge University Press 2017.

5. Binkley N, Blank RD, Leslie WD, et al. Osteoporosis in Crisis: It’s time to focus on fracture. J Bone Min Res. 2017; 32: 1391-1394.

6. Yuksul N, Charrois TL. Osteoporosis. In: Mahmoud SD (ed.). Patient assessment in Clinical Pharmacy. https://link.springer.com/chapter/10.1007%2F978-3-030-11775-7_18. Accessed Nov. 5, 2020.

7. Osteoporosis Canada. The osteoporosis care gap. Available at https://fls.osteoporosis.ca/the-osteoporosis-care-gap/. Accessed Nov. 5, 2020.

8. Rosen CJ. The Epidemiology and Pathogenesis of Osteoporosis. [Updated 2020 Jun 21]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext. [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000.

9. Cosman F, de Beur SJ, LeBoff MS, et al., Clinicians guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014; 25: 2359-2381. Available at https://link.springer.com/article/10.1007/s00198-014-2794-2. Accessed Sept. 2, 2020.

10. National Bone Health Alliance and American Academy of Family Physicians. Bridging the osteoporosis screening, diagnosis and treatment gap in primary care. Available at: https://www.aafp.org/dam/AAFP/documents/about_us/strategic_partnerships/amgen/bridging-gap.pdf. Accessed Sept. 2, 2020.

11. Osteoporosis Canada. The Problem: Post-Fracture Care Gap.

12. Hopkins RB, Burke N, Von Keyserlingk C, et al. The current economic burden of illness in Canada. Osteoporosis Int. 2016; 27: 3023-3032.

13. Osteoporosis Canada. Osteoporosis drug treatments and medication during COVID-19. April 2020. Available at: https://osteoporosis.ca/osteoporosis-drug-treatments-medication-during-covid-19/ . Accessed Sept. 2, 2020.

14. Osteoporosis Canada. Fast facts. Available at: https://osteoporosis.ca/about-the-disease/fast-facts/. Accessed Sept. 2, 2020.

15. Yu M, Downey C, Torralba KD. The Fracture Liaison Service to close the osteoporosis care gap: a leadership educational model for undergraduate and postgraduate trainees. Clin Rheum. 2020; 39: 619-626.

16. Osteoporosis Canada. Report from Osteoporosis Canada’s first national FLS audit: leading FLS improvement in Canada. September 2018. Available at: https://fls.osteoporosis.ca/wp-

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content/uploads/Report-from-Osteoporosis-Canadas-first-national-FLS-audit.pdf. Accessed Sept. 2, 2020.

17. Folin SL, Hansen LB. Current approaches to the prevention and treatment of postmenopausal osteoporosis. Am J Health Syst Pharm 2003; 60. Available at https://www.medscape.com/viewarticle/453035_11. Accessed Sept. 2, 2020.

18. Hanley DA. Osteoporosis. In: Therapeutic Choices. 2017. Canadian Pharmacists Association, Ottawa ON.

19. Drake MT, Clarke Bl, Khosla S. Bisphosphonates: Mechanism of action and role in clinical practice. May Clin Proceeding. 2008; 83: 1032-1045.

20. Streicher C, Heyny A, Andrukhova O, et al. Estrogen regulates bone turnover by targeting RANKL expression in bone lining cells. Scientific Reports 2017; 7: Article Number 6460 Available at https://www.nature.com/articles/s41598-017-06614-0. Accessed Sept. 2, 2020.

21. Forteo product monograph.

22. Evenity product monograph.

23. ACH-alendronate product monograph.

24. Actonel product monograph.

25. ACT Etidrocal product monograph.

26. Aclasta product monograph.

27. Prolia product monograph.

28. Pedersen AB, Heide-Jorgenson U, Sorenson HT. Comparison of risk of osteoporotic fracture in denosumab vs alendronate treatment within 3 years of initiation. JAMA Network Open. 2019; 2(4): e192416. Doi:10.1001/jamanetworkopen.2019.2416.

29. Evista product monograph.

30. C.E.S. (conjugated estrogens oral tablets) product monograph.

31. Estrace product monograph.

32. Climara product monograph.

33. Estradot product monograph.

34. International Osteoporosis Foundation. Hormone Replacement Therapy (HRT). Available at https://www.iofbonehealth.org/hormone-replacement-therapy-hrt. Accessed Sept. 2, 2020.

35. Eastell R, Walsh JS. Anabolic treatment for osteoporosis: teriparatide. Clin Cases in Min and Bone Metab. 2017; 14: 173-178.

36. McClung MR. Romosuzumab for the treatment of osteoporosis. Osteoporosis and Sarcopenia. 2018; 4: 11-15.

37. Sang KG, Petersen J, Brandi ML, et al. Romosuzumab or alendronate for fracture prevention in women with osteoporosis. New Engl J Med. 2017; 377: 1417-1427.

38. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. New Engl J Med. 2016; 375: 1532-1543.

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39. Cunha JP. Evenity. Rxlist. 2019 Available at https://www.rxlist.com/evenity-side-effects-drug-center.htm. Accessed Sept. 2, 2020.

40. Kendler DL, Adachi JD, Brown JP, et al. A scorecard for osteoporosis in Canada and seven Canadian provinces. Osteoporos Int (2020). https://doi.org/10.1007/s00198-020-05554-2. Accessed Sept. 2, 2020.

41. Papaioannou A, Morin S, Cheung AM, et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 2010; 182: 1864-1873. Available at https://www.cmaj.ca/content/182/17/1864. Accessed Sept. 2, 2020.

42. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2020. Endocrine Practice 2020; 26 (Suppl 1): 1-39. Available at https://www.aace.com/disease-state-resources/reproductive-and-gonad/clinical-practice-guidelines-recent-news-and-updates. Accessed Sept. 2, 2020.

43. Papaioannou A, Santesso N, Morin SN, et al. Recommendations for preventing fracture in long-term care. CMAJ 2015; 187: 1135-1144. Available at https://www.cmaj.ca/content/cmaj/187/15/1135.full.pdf. Accessed Sept. 2, 2020.