Bones, as reservoirs of calcium and phosphorus, continuously remodel to maintain strength and function.1 However, suboptimal peak bone mass in young adulthood, excessive resorption of bone, or impaired bone formation during remodeling can result in osteoporosis.
Osteoporosis is a skeletal disorder in which bone density and quality are reduced. Patients experience loss of bone mass, deterioration of bone tissue, and a decline in bone quality, which leads to increased bone fragility and a higher risk of fractures.2
Peak bone density occurs in a person’s early 20s and declines by the decade.1 According to a 2014 National Osteoporosis Foundation report, 10.2 million adult Americans had osteoporosis and another 43.4 million had low bone mass by age 50 years. It is predicted that by 2030, this prevalence will increase to 71 million patients with or at risk for osteoporosis. The prevalence of osteoporosis rises with increasing age, with the highest incidence of osteoporosis being 16.4% in patients between 70 and 79 years of age and 26.2% in patients older than 80 years of age.
As a result of menopause, women are more prone than men to develop osteoporosis (15.4% vs. 4.3%, respectively), with onset often at an earlier age. Mexican Americans have the highest prevalence (13.4%), followed by non-Hispanic whites (10.2%) and Asians (8.9%). Non-Hispanic Blacks have the lowest prevalence (4.9%).3 Falls and subsequent osteoporotic fractures lead to significant morbidity and mortality; mortality risk ranges between 21% and 30% within the first year of the fracture, depending on the site.3-5
Among Caucasian adults ages 50 years and older in the United States, about 50% of women and 20% of men will experience an osteoporotic fracture in their remaining lifetime; however, fracture rates differ by ethnic/racial population and skeletal site. Annual fracture-related costs are expected to increase from $57 billion to more than $95 billion by 2040.6
Therefore, it is imperative that primary care providers address this challenge by implementing practices to screen patients for osteoporosis to prevent and/or treat the disorder and subsequent comorbidities.
Pathophysiology
Bone architecture consists of a matrix formed by collagen protein deposited with mineral crystal hydroxyapatite formed by calcium and phosphate. Osteoporosis ensues as the result of an imbalance between bone resorption and bone formation. Osteoclasts promote bone resorption while osteoblasts facilitate bone formation. Increased bone resorption with a lack of compensation in formation is the most common cause of osteoporosis. Additionally, protein catabolic disorders can be major contributors to secondary osteoporosis. Decreased mineralization, rickets, and osteomalacia also affect architecture and bone strength, leading to fractures.
Hormones play a major role in bone remodeling. Parathyroid hormone as a whole 84 amino acid molecule promotes resorption, whereas its fraction of amino acids 1-34, calcitonin, and receptor activator of nuclear factor kappa-B (RANK)/receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin system facilitate bone formation.7-13 Additionally, vitamin D, fibroblast growth factor (FGF) 23, and osteocalcin affect mineralization.14-18 Hence, disorders involving these hormones and factors contribute to low bone mass and/or architecture, resulting in a predilection toward fractures.
The bone-specific enzyme alkaline phosphatase also induces bone formation. Therefore, serum alkaline phosphatase concentration rises with growing bone during adolescence as well as with disorders inducing bone formation (e.g., osteoblastic metastasis, acromegaly, osteomalacia, Paget’s disease, etc). In contrast, congenital deficiency, or total absence of this enzyme, known as hypophosphatasia, manifests as juvenile osteoporosis.
Risks Factors and Causes
Low bone mass and osteopenia/osteoporosis are used synonymously, although decreased mineralization also may be a contributing feature. An increased risk of osteoporosis has been linked to multiple factors. (See Table 1.) Thus, it may be classified as primary or idiopathic if the cause is not recognized and deemed to be secondary based on the cause of decreasing bone mass.
Several conditions and diseases cause or contribute to osteoporosis and fractures, including endocrine, gastrointestinal, rheumatologic, and autoimmune diseases, as well as neurological and musculoskeletal disorders. Numerous lifestyle factors and medications also contribute to increased risks for both osteoporosis and fracture. (See Table 1.) Therefore, a thorough evaluation for the presence of pathophysiologic factors and pathogenic disorders that cause or contribute to decreased bone mass plays an integral part in increasing screening and surveillance, as well as prevention and diagnosis of osteoporosis.
Manifestations
Osteoporosis or osteopenia is asymptomatic in many people and often is detected during screening because of the presence of well-established risk factors. (See Table 1.)
Table 1. Factors that Cause or Contribute to Low Bone Density, Including Osteoporosis |
|
Lifestyle factors |
Alcohol abuse, smoking (active or passive), frequent falling, immobilization, inadequate physical activity, excess vitamin A, vitamin D insufficiency or deficiency, low calcium intake, excessive thinness, high salt intake |
Endocrine disorders |
Central obesity, hyperparathyroidism, hyperthyroidism, Cushing's syndrome or disease, diabetes mellitus (types 1 and 2), hypogonadism, pheochromocytoma |
Gastrointestinal disorders |
Celiac disease, inflammatory bowel disease, primary biliary cirrhosis, gastric bypass, malabsorption, gastrointestinal surgery, pancreatic disease |
Rheumatologic and autoimmune diseases |
Rheumatoid arthritis, ankylosing spondylitis, systemic lupus, other rheumatic and autoimmune diseases |
Neurological and musculoskeletal risk factors |
Epilepsy, Parkinson’s disease, multiple sclerosis, spinal cord injury, stroke, muscular dystrophy |
Miscellaneous conditions and diseases |
AIDS/HIV, amyloidosis, chronic obstructive lung disease, congestive heart failure, metabolic or renal tubular acidosis, depression, end-stage renal disease, hypercalciuria, idiopathic scoliosis, post-transplant bone disease, sarcoidosis, weight loss, eating disorders, mastocytosis, chronic liver disease, malnutrition, congenital disorders, osteogenesis imperfecta, hypophosphatasia |
Medications |
Aluminum (in antacids), anticoagulants (heparin), anticonvulsants, aromatase inhibitors, barbiturates, chemotherapeutic drugs, depot medroxyprogesterone, glucocorticoids (> 5 mg/day prednisone or equivalent for > 3 months), gonadotropin-releasing hormone agonists, lithium, cyclosporine and tacrolimus, methotrexate, parenteral nutrition, proton pump inhibitors, selective serotonin reuptake inhibitors, tamoxifen, thiazolidinediones, SGLT2 inhibitors, thyroid hormones (in excess) |
AIDS: acquired immunodeficiency syndrome; HIV: human immunodeficiency virus; SGLT2: sodium-glucose cotransporter-2 |
|
Major manifestations include pain, fractures, and deformities as well as their consequences (e.g., cor pulmonale secondary to restrictive pulmonary disease caused by kyphoscoliosis resulting from thoracic vertebral fractures or pulmonary embolism because of immobilization caused by a hip fracture).
Screening and Diagnosis
Osteoporosis is a preventable and treatable disorder. Screening is an integral part of prevention and treatment. The screening process is essential in identifying patients with osteoporosis in the early phase of the disease when therapy is most effective.1
The Bone Health and Osteoporosis Foundation (BHOF; previously National Osteoporosis Foundation) and American Association of Clinical Endocrinologists/American College of Endocrinologists recommend that all postmenopausal women and men 50 years of age and older be assessed for osteoporosis risk factors to determine the need for bone mineral density (BMD) testing and/or vertebral imaging.2,19
The U.S. Preventive Services Task Force advises all women older than 65 years of age and men older than 70 years of age to undergo BMD testing. It also recommends bone density assessment in younger women whose fracture risk is equal to or greater than that of a 65-year-old white woman and who have no additional risk factors.3 BMD examination is not recommended in children, adolescents, and healthy young men or premenopausal women unless there is a history of fracture secondary to a trivial trauma or other risk factors for bone loss, including congenital disorders such as osteogenesis imperfecta or hypophosphatasia.2
Screening for osteoporosis risk factors in appropriate populations is essential to identify at-risk patients who would benefit from BMD testing or vertebral imaging. When screening for osteoporosis, providers should take a thorough history, including recent loss of height or spinal deformity; perform a detailed physical examination, including height measurement; and assess for the presence of secondary causes of osteoporosis.
Providers also should conduct a clinical fracture risk assessment with a validated tool, such as the Fracture Risk Assessment (FRAX) tool or the Garvan risk calculator.19-20 The FRAX tool is the most widely used questionnaire to screen patients for fracture risk. In 2008, the World Health Organization (WHO) developed the FRAX tool to predict the 10-year probability of a hip, spine, wrist, or humeral fracture.19
The FRAX tool incorporates various risk factors for osteoporosis and is intended for use in postmenopausal women and in men 50 years of age and older. (See Table 2.) It may underestimate the risk of a future fracture in patients with an increased risk of falls, a recent fracture, and previous multiple fractures as a result of osteoporosis.
Table 2. FRAX Tool Risk Factors |
|
FRAX: Fracture Risk Assessment |
Dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring BMD for the diagnosis of osteoporosis, predicting future fracture risk, and monitoring the effect of therapy. BMD often is determined at multiple sites, including femoral neck, total hip and/or spine, and, occasionally, forearm. Quantitative computed tomography (CT) scan is an alternative recommended technique. Quantitative CT scans provide three-dimensional volumetric measurements, while DEXA determines calcium content per area unit and, thus, is two-dimensional. However, DEXA has become the tool of choice because of its convenience and cost. Moreover, DEXA has been used in almost all clinical trials assessing the efficacy of most therapies.
BMD measurement via DEXA is reported as calcium, g/m2 bone surface area, as well as T-score and Z-score.20 The T-score is the standard deviation of the patient’s BMD from the mean value for healthy young white women 20 to 29 years of age, with no adjustments for postmenopausal women and men 50 years of age or younger, irrespective of race, nationality, or ethnicity.
The Z-score indicates the patient’s BMD in comparison to mean BMD for a healthy, age-matched reference population with the same sex and ethnicity.1,19,20 The Z-score is reported mainly for children, men 50 years of age or younger, and premenopausal women, and if a secondary cause of osteoporosis is present.21
In a postmenopausal woman with a very low Z-score, the clinician should evaluate the patient further to determine if a secondary cause also is present.19 The WHO T-score classification criteria provide the thresholds for classification of low bone mass into groups for determination of appropriate therapeutic approach. (See Table 3.) Of note, BMD is sensitive but not specific for the diagnosis of osteopenia or osteoporosis.
Table 3. World Health Organization Criteria for Classification of Osteoporosis |
|
Normal |
T-score -1.0 or above |
Low bone mass (osteopenia) |
T-score between -1.0 and -2.5 |
Osteoporosis |
T-score -2.5 or below |
Severe or established osteoporosis |
T-score -2.5 or below with ≥ 1 fracture |
Low bone density indicates the presence of osteoporosis or osteopenia but also may indicate osteomalacia and lytic disorders. Additional laboratory tests are essential to differentiate these disorders. Normal serum calcium, phosphorus, and alkaline phosphatase concentrations indicate the presence of osteopenia or osteoporosis, whereas subnormal calcium, phosphorus, and/or vitamin D, as well as elevated alkaline phosphatase, help make the diagnosis of osteomalacia.
Other laboratory tests helpful for diagnosis include serum markers of bone resorption or products of collagen breakdown (e.g., parathyroid hormone, telopeptides, and urinary hydroxyproline) and indicators of bone formation (e.g., bone-specific alkaline phosphatase, osteoprotegerin, phosphorus).1,19 Finally, determination of serum concentrations of calcium, vitamin D and its metabolites, fibroblast growth factor 23 (FGF-23), and osteocalcin provide the status of mineralization.14-18
In a susceptible population with risk factors, the diagnosis of osteoporosis is confirmed in adults by BMD measurement or by the occurrence of a low-trauma hip or vertebral fracture not caused by a major event such as a motor vehicle accident.2
Vertebral fractures often are asymptomatic and may remain undiagnosed for many years. Vertebral imaging with a lateral thoracic and lumbar spine X-ray confirms these fractures in at-risk patients. Another option is a vertebral fracture assessment (VFA), a test simultaneously conducted with the DEXA to detect abnormal compression of spinal vertebral bodies.19 See Table 4 for a breakdown of which patients should receive vertebral imaging or VFA as well as BMD measurement.
Table 4. Patients Who Should Receive Vertebral Imaging or Vertebral Fracture Assessment as Well as Bone Mineral Density Measurement |
|
S/P: status post |
Preventing Bone Loss and Fractures
A patient-centered approach is an integral part of osteoporosis management. Lifestyle modifications tailored to individual needs play a major role in preventing bone loss and protecting against future fractures. Lifestyle modifications to improve bone health include avoiding caffeine, alcohol, and active and passive exposure to tobacco smoke.21-23
Caffeine consumption has been linked to decreased calcium absorption in the gut and, thus, an increased risk of bone loss and fractures.2,19,20,22 Patients should be advised to discontinue or limit caffeine intake to fewer than two servings per day.22
Excess alcohol consumption must be discouraged because it is associated with an increased risk of fracture attributed to multiple factors.23 Alcohol intake is documented to decrease calcium intake and promote deleterious effects on bone formation.23 Moreover, alcohol increases one’s predisposition to falls, leading to fractures.23 Therefore, the BHOF recommends avoidance of excessive alcohol intake for patients who have or are at risk for osteoporosis. Likewise, BHOF recommends total tobacco cessation since smoking one pack of cigarettes daily in adulthood has been associated with a 5% to 10% reduction in BMD.2,17,21
Other recommended lifestyle changes involve recommending resistance and weight-bearing exercises, which are well-established to increase BMD, improve balance, and reduce the risk of falls, thus resulting in prevention of fractures.24,25 In prospective cohort studies, exercise was well-documented to reduce the overall risk of fracture in older adults.24-27 One study suggests the most effective exercise for improving BMD of the femoral neck was non-weight-bearing, high-force exercise such as resistance strength training, while a combined program of more than one exercise type was beneficial for lumbar spine BMD.2,19,26,27
Adequate vitamin D intake is crucial to maintaining bone health, since it is essential for bone mineralization. Vitamin D deficiency is observed frequently in patients with osteoporosis and leads to a further decline in BMD, predisposing to fractures, especially of the hips.21 Therefore, vitamin D supplementation often is recommended in patients with vitamin D insufficiency or deficiency.2,28-34
Vitamin D deficiency can occur because of a limited intake of food products with high vitamin D content, as well as a lack of direct exposure to ultraviolet rays in sunlight as the result of an inadequate number of sunny days in certain geographic locations.28-33 Alternatively, reduced absorption by the skin, because of the use of sunscreens recommended for prevention of skin cancers as well as increased dermal pigment in populations with darker skin, also are associated with vitamin D deficiency.
Daily therapeutic doses of vitamin D vary among individuals because of factors such as race, diet, medication interactions, and comorbid conditions.28-31 Recent data suggest the adequate dose of vitamin D3 cholecalciferol required to correct deficiency varies depending on the severity of deficiency and, thus, often is greater than 1,000 IU daily.30,31 Alternatively, long-acting vitamin D2 ergocalciferol may be administered once or twice weekly to treat deficiencies.
Occasionally, physiologically active 1,25 hydroxyvitamin D3 may be required, especially in patients with deficiency induced by steroids or chronic renal failure, as well as following organ transplantation.34 It is important to note that vitamin D supplementation alone has not been shown to increase BMD or reduce the risk of fracture.32,33
Adequate calcium intake is another essential component in preserving bone mineralization and therefore plays a major role in prevention and treatment of osteoporosis. The recommended daily elemental calcium intake derived from diet, supplements or both is 1,200 mg for women ≥ 50 years of age and men ≥ 70 years of age; 1,000 mg daily is recommended for men 51-70 years of age.30,31,33
Elemental calcium accounts for a certain fraction of a tablet containing calcium salt (e.g., calcium carbonate or citrate) and, therefore, is not the dose of the full tablet. Appropriate calcium intake increases BMD and reduces fractures in conjunction with other therapeutic modalities.2,19,33 Patients receiving adequate daily calcium amounts (1,000 mg to 1,200 mg) from their diet do not require calcium supplements. However, those with inadequate intake should increase their daily intake of calcium-containing foods or take supplemental elemental calcium (generally 500 mg/day to 1,000 mg/day) in divided doses at mealtime.
The risks of excessive calcium intake are unclear. Intake of larger quantities is not more effective in improving BMD and may be detrimental because of the promotion of renal calculi secondary to enhanced renal excretion, increased gastric acid secretion, and cardiovascular calcification.31,32
Many calcium supplement options are available. Calcium carbonate is an inexpensive option and contains a large amount of elemental calcium. It requires adequate gastric acid for absorption and is best taken with meals. In patients with higher gastric pH, such as older adults or those on acid-suppressing therapy, calcium citrate may be a more effective option. However, it may be more expensive and contains less elemental calcium. In addition to tablets, soft chew and gummy options recently have become available.2,19,31
Treatment
Osteoporosis treatment focuses on both nonpharmacologic and pharmacologic approaches. The goals of osteoporosis therapy include lowering osteoporosis-related morbidity and mortality by preventing fractures and deformities, as well as improving quality of life as a result of increasing bone mass or, at least, reducing bone loss.
In addition to lifestyle measures detailed earlier, pharmacologic therapy is indicated in adults with a history of fragility fracture or those with established osteoporosis documented by BMD with a T-score ≤ -2.5. People at high risk for fracture are defined by BMD with a T-score between -1.0 and -2.5 combined with a 10-year probability of hip fracture of ≥ 3% or major osteoporotic fracture of ≥ 20% as determined by the FRAX tool; pharmacologic therapy also should be encouraged for these patients.2,19
Pharmacologic agents for treating osteoporosis are classified as either antiresorptive (inhibiting osteoclast-mediated bone resorption) or anabolic (stimulating osteoblasts to enhance bone formation). Both groups of agents are documented to improve BMD and reduce fractures.35 However, large comparative studies of safety and efficacy are lacking. Cost, convenience, and other patient preferences, including compliance and adherence, often are influential factors in a patient-centered approach.
Bisphosphonates
Evidence-based guidelines state that bisphosphonates should be considered as initial therapy because of the mechanism of action enhancing bone resorption in most patients with osteoporosis.2,19,36 These agents inhibit osteoclast activity and have been shown to improve BMD and reduce fractures.35,37-40 Several bisphosphonates, including generic formulations, are available and approved for both prevention and treatment. (See Table 5.)
Table 5. Pharmacologic Agents for the Treatment of Osteoporosis |
||||
Medication |
Brand Name |
FDA Indication |
Dosing Regimen |
Adverse Effects |
Oral Biphosphonates |
||||
Alendronate |
Fosamax |
Prevention and treatment of hip, vertebral, and nonvertebral fractures |
Prevention: 5 mg daily or 35 mg weekly Treatment: 10 mg daily or 70 mg weekly |
Common: Mild upper gastrointestinal events,muscular and joint pains, hypocalcemia, headache
Rare: Atypical femur fractures, osteonecrosis of the jaw, esophageal ulcerations, perforations, bleeding events |
Fosamax Plus D |
Treatment of hip, vertebral, and nonvertebral fractures |
70 mg + 2,800/5,600 IU weekly |
||
Ibandronate |
Boniva |
Prevention and treatment of only vertebral fractures |
150 mg monthly or 2.5 mg daily |
|
Risedronate |
Actonel; Actonel with calcium |
Prevention and treatment of hip, vertebral, and nonvertebral fractures |
5 mg daily or 35 mg weekly or 75 mg x 2 days monthly or 150 mg monthly; 35 mg once weekly + 1,250 mg calcium x 6 days weekly |
|
Risedronate, delayed release |
Atelvia |
Treatment of hip, vertebral, and nonvertebral fractures |
35 mg weekly |
|
IV Biphosphonates |
||||
Zoledronic acid |
Reclast |
Prevention and treatment of hip, vertebral, and nonvertebral fractures |
Prevention: 5 mg every 2 years Treatment: 5 mg yearly |
Common: Muscle and joint pain, acute flu-like reaction Rare: Atypical femur fractures, osteonecrosis of the jaw, acute renal failure |
Ibandronate |
Boniva |
Treatment of only vertebral fractures |
3 mg every 3 months |
|
Selective Estrogen-Receptor Modulator (SERM) |
||||
Raloxifene |
Evista |
Prevention and treatment of only vertebral fractures |
60 mg PO daily |
Common: Hot flashes Rare: Pulmonary embolism, thrombotic events |
FDA: Food and Drug Administration; PO: by mouth; SC: subcutaneously; IV: intravenous |
||||
Table 5. Pharmacologic Agents for the Treatment of Osteoporosis (continued) |
||||
Medication |
Brand Name |
FDA Indication |
Dosing Regimen |
Adverse Effects |
Conjugated Estrogen/SERM |
||||
Conjugated estrogen/ bazedoxifene |
Duavee |
Prevention of only vertebral fractures |
Conjugated estrogen 0.45 mg/bazedoxifene 20 mg PO daily |
Common: Hot flashes Rare: Pulmonary embolism, thrombotic events |
Recombinant Calcitonin |
||||
Calcitonin |
Miacalcin |
Treatment of only vertebral fractures |
200 IU intranasal daily |
Common: Nasal congestion, nausea, flushing, injection site reaction |
Parathyroid Hormone Agents |
||||
Abaloparatide |
Tymlos |
Treatment of vertebral and nonvertebral fractures in high-risk patients |
80 mcg SC daily |
Common: Arthralgia, pain, headache, nausea, orthostatic hypotension, hypercalcemia, hyperuricemia Rare: Osteosarcoma |
Teriparatide |
Forteo |
Treatment of vertebral and nonvertebral fractures in high-risk patients |
20 mcg SC daily |
|
RANKL Inhibitor |
||||
Denosumab |
Prolia |
Treatment of hip, vertebral, and nonvertebral fractures |
60 mg SC every six months |
Common: Muscle and joint pain, hypocalcemia, skin reactions, headache Rare: Osteonecrosis of the jaw, cellulitis |
Anti-Sclerostin Antibody |
||||
Romosozumab |
Evenity |
Treatment of osteoporosis in postmenopausal women at high risk of fracture |
105 mg SC injection x 2 monthly for 12 months |
Common: Injection site reactions, bone pain Rare: Serious cardiovascular events (myocardial infarction, stroke, cardiovascular death) |
FDA: Food and Drug Administration; PO: by mouth; SC: subcutaneously; RANKL: receptor activator of nuclear factor kappa-B ligand |
||||
Oral formulations may appear as a convenient option, but bioavailability following oral administration is relatively poor when compared with intravenous (IV) preparations. Moreover, oral bisphosphonates must be administered on an empty stomach for maximal absorption.1,19,35,39
Therefore, patients should take oral bisphosphonates before food, often in the morning upon awakening with at least eight ounces of water. Patients also must remain upright for 30 to 45 minutes to minimize the risk of esophagitis either caused by reflux or the tablet remaining in and irritating the esophagus. Finally, patients should be reminded to wait at least 30 minutes before consuming food, drinks, or any other medications or supplements to enhance the drug’s absorption. Because of these stringent requirements, compliance and adherence to oral bisphosphonates is relatively low compared to IV bisphosphonates, which also allows for less frequent administration.
Oral bisphosphonates should be avoided in patients with active esophageal disorders, such as achalasia, stricture, varices, or dysmotility, as well as in those receiving agents for peptic diseases. Moreover, oral agents are contraindicated in patients with a history of gastrointestinal maldigestion or malabsorption and those who are unable to remain upright for 30 to 45 minutes after oral administration; these patients are suitable candidates for administration of IV formulations.
Bisphosphonates must not be used in patients with estimated glomerular filtration rate < 30 mL/min to 35 mL/min, as well as those with documented hypersensitivity. Monitoring for and correction of hypocalcemia and vitamin D deficiency is essential prior to and during oral or IV bisphosphonate administration to prevent hypocalcemia.
Side effects of bisphosphonate therapy include acute-phase reaction, a flu-like syndrome that can occur with both IV and high-dose oral administration.35,37-40 The prevalence of this syndrome declines with repeated administration.
Gastrointestinal side effects, such as esophagitis, diarrhea, and heartburn, are common following administration of oral forms. Hypocalcemia is a potential risk, albeit rare in the presence of normal vitamin D levels prior to administration of bisphosphonates. Post-marketing reports have documented the occurrence of bone, joint, and muscle pain, as well as atrial fibrillation.35,37,38 Rarely, atypical femoral fractures have been reported.41-43 However, pathophysiology of these fractures is poorly understood and is speculated to be secondary to concurrent presence of other bone disorders causing bone loss, including osteomalacia, steroid therapy, and hyperparathyroidism, as well as prolonged duration of use.41,43
Atypical fractures are reported to be less frequent in younger men compared to older women.43 Moreover, the occurrence of these fractures appears to be drug dependent. The frequency of occurrence is reported most commonly with alendronate, followed by risedronate and zoledronic acid.41
Osteonecrosis of the jaw is an even rarer reported side effect.19,44-47 In most reports, osteonecrosis of the jaw is documented to occur with administering bisphosphonates to patients with malignancies or other cathectic disorders.45,47 The American Association of Oral and Maxillofacial Surgeons notes in a 2022 position paper that the prevention strategies related to dental surgery in patients using antiresorptive therapy are controversial; data recommending cessation of osteoporosis therapy prior to dental surgery remain inconclusive. A multidisciplinary approach, consisting of risk stratification, dental health education, and optimal surgical strategies, is recommended.44
Denosumab
Denosumab is a human monoclonal antibody that targets RANKL, thereby preventing osteoclast formation.10-12 Denosumab has been shown to improve BMD and reduce the incidence of new vertebral and nonvertebral fractures, including hip fractures, in postmenopausal women.2,19,48,49 It appears to be a reasonable alternative in patients who may not be appropriate candidates for biphosphonates, such as those with reduced renal function or those who have contraindications to oral bisphosphonates.
Of note, in 2023, the American College of Physicians recommended denosumab as second-line therapy behind bisphosphonates, mostly because of the higher long-term costs with denosumab compared to bisphosphonates.36
Denosumab 60 mg is administered subcutaneously in an office setting every six months. Patients should be strongly encouraged to adhere to injections every six months to avoid fractures related to delayed administration. As with bisphosphonates, calcium and vitamin D deficiencies must be corrected prior to administration of denosumab.
Atypical femur fracture and osteonecrosis of the jaw are reported occasionally, as with bisphosphonates.43-45,47 Few small studies have indicated an increased risk of infection (cellulitis, pancreatitis, endocarditis) with the use of denosumab, although causality remains to be determined.2,19,48-50 When treatment with denosumab is stopped after two years, BMD values return to baseline or worse; therefore, a “drug holiday” is not recommended for denosumab.50,51
Estrogen and Selective Estrogen-Receptor Modulators
Estrogen replacement therapy is known to prevent bone resorption and maintain bone structure. In the Women’s Health Initiative (WHI) trial, estrogen therapy significantly reduced the incidence of vertebral and nonvertebral fractures, including hip fractures.54,55 This finding is consistent with data in several previous trials.56 Thus, estrogen replacement therapy is well established to show a distinct benefit to bone structure and improve fracture outcomes. However, long-term estrogen replacement therapy appears to increase the risk of breast cancer incidence, as documented in the WHI, although without raising mortality.
Some experts believe that a lack of increased mortality may be the result of increased surveillance and unmasking of cancer in the very early stage of the disease. Furthermore, a slightly increased risk of breast cancer was neutralized by a decline in colorectal cancers of similar degree in the WHI trial.54,55 Finally, an increase in negative cardiovascular outcomes noted in the initial WHI data was refuted by the same authors later because of the finding that initiation of hormone replacement therapy (HRT) in the perimenopausal years actually reduced cardiovascular events, including mortality, as documented in several previous observational studies.56 Moreover, the maximum benefits regarding bone health seem to be following initiation of HRT in women during the perimenopausal period.54-56
Another established side effect of estrogen use is a significant rise in thromboembolic events, especially in the first two years following initiation of HRT.57,58 However, these events can be minimized by simultaneous daily administration of aspirin 81 mg to 162 mg. Therefore, the U.S. Food and Drug Administration (FDA) has approved HRT for the prevention and treatment of osteoporosis beginning in the perimenopausal years. However, some experts still recommend that HRT should be reserved only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.55,56
Selective estrogen-receptor modulators (SERMs) activate distinctly selective tissue receptors for estrogen in bone, resulting in decreased bone resorption and increased bone density. Alternatively, they act as estrogen receptor blockers at certain sites, thus inhibiting estrogen activity in some tissues, primarily in breast tissue but also in the vasculature.59-64 Therefore, SERMs are effective in preventing or delaying recurrence of estrogen-responsive breast cancers and are approved for this indication by the FDA.59-61
Because of these dual opposing effects, side effects include thromboembolic disorders and possibly uterine cancer similar to unopposed estrogen receptor therapy, as well as hot flashes and night sweats caused by estrogen receptor blockade.62,63
Raloxifene alone is FDA-approved for the prevention and treatment of osteoporosis, since it demonstrated a reduced risk of spinal fractures in clinical trials, despite a lack of evidence in terms of benefit for nonvertebral sites, including the hip.19,59,60 Therefore, in women with low bone density and a history of or susceptibility to breast cancer because of family history, raloxifene may be a drug of choice to prevent the onset of both osteoporosis and breast cancer, as well as recurrence of the latter since it demonstrated significant reduction in breast cancer in an osteoporosis trial.59,60 When raloxifene therapy is discontinued, the BMD benefits are lost quickly during the next one to two years.19
The combination of an alternative SERM bazedoxifene with estrogen was approved recently for treating menopausal symptoms and preventing osteoporosis, but not for the treatment of osteoporosis.64 Available data show that estrogen and bazedoxifene separately prevent vertebral fractures, and the combination has shown an improvement in BMD; however, to date, data proving fracture prevention for the combination are lacking.64 The breast cancer risk for this combination is unknown, and common adverse effects consist of muscle cramps, nausea, abdominal pain, diarrhea, and oropharyngeal pain. Increased risks of stroke and venous thromboembolic disease also are documented.62,63
Calcitonin
Injectable and nasal formulations of recombinant salmon calcitonin are FDA-approved for treating postmenopausal osteoporosis. The daily nasal spray and subcutaneous injection inhibit osteoclastic bone resorption, although the efficacy of decreased fracture occurrence is evident only in new vertebral compression fractures as opposed to hip or other nonvertebral fractures.65-69
Its effect on BMD is relatively modest compared to other agents, making it a suboptimal initial choice for treatment; however, it can be used when contraindications to first-line therapy are present. Its adverse effect profile is acceptable, with nasal irritation and rhinitis noted with use of a nasal formulation. Subcutaneous administration may cause transient local irritation and pain. A meta-analysis of nasal spray calcitonin showed a higher incidence of malignancy, although the FDA found no evidence of a causal relationship.
When calcitonin treatment is stopped, BMD benefits are lost within the first one to two years.66,67 Because of reported analgesic effects, calcitonin may be used for relief of pain caused by fractures, especially vertebral compression fractures.65-69
Anabolic or Bone-Forming Drugs
Two parathyroid-hormone-simulating agents are approved for treatment of osteoporosis. Teriparatide, which has been available since 2002, is a recombinant fractionated molecule of human parathyroid hormone consisting of 34 amino acids. It is effective as an anabolic agent by stimulating osteoblast regeneration and function, in contrast to the whole parathyroid hormone molecule comprised of 84 amino acids known to promote bone resorption.70-72 It also is likely to enhance mineralization by increasing circulating calcium via promoting gastrointestinal calcium absorption and facilitating renal tubular resorption of calcium. Alternatively, abaloparatide, which was approved in 2017, is a synthetic peptide of human parathyroid hormone-related protein.73,74
Neither agent is a preferred initial option for osteoporosis unless antiresorptive agents (e.g., bisphosphonates or denosumab) are contraindicated or an indication related to diminished bone formation (e.g., osteogenesis imperfecta) is present.70-74 Rather, they often are reserved for men or postmenopausal women with severe osteoporosis, a T-score of -3.5 or below in the absence of fracture, or a T-score of -2.5 or below plus an acute fragility fracture.70-76
Daily subcutaneous administration of these agents has demonstrated efficacy in reducing the risk of vertebral and other fractures, but not hip fractures in postmenopausal women with osteoporosis.19,70-74
Short-term adverse effects are mild and transient and include nausea, orthostatic hypotension, and leg cramps. Hypercalcemia is reported rarely. Contraindications include hypercalcemia of any etiology. Primary hyperparathyroidism and hyperparathyroidism secondary to chronic renal failure result in decreased efficacy of these agents.
These drugs may be used after resolution of the disorders causing hypercalcemia and secondary hyperparathyroidism (e.g., vitamin D deficiency). Therefore, laboratory testing including serum calcium, vitamin D, and parathyroid hormone levels, as well as markers of renal function, must be performed prior to administration.
Both agents have a boxed warning because of a documented occurrence of osteosarcoma in rats, and they are contraindicated in patients at increased risk of osteosarcoma (e.g., Paget’s disease, open epiphyses, history of irradiation involving the skeleton, or unexplained elevation of alkaline phosphatase level). Currently, these agents are not indicated for treatment beyond two years because of this concern.70-74
After discontinuation of teriparatide or abaloparatide, BMD declines quickly, although fracture reduction benefit may remain for one to two years.75,76 Using alendronate or other bisphosphonates after cessation of parathyroid hormone-related agents can prevent this BMD loss and may be associated with further increases in BMD.19,38,39,77-79 Therefore, therapy with antiresorptive agents (e.g., bisphosphonates) is strongly recommended for two years after treatment with teriparatide or abaloparatide.19,70-76
Romosozumab
Romosozumab is a newer, unique agent in that it both increases bone formation and decreases bone resorption. It works as a monoclonal anti-sclerostin antibody. Sclerostin is produced by osteocytes and inhibits bone formation. By binding to and blocking this protein, osteoblast activity is increased while slowing bone breakdown.
Trials of romosozumab show a reduction in vertebral and nonvertebral fractures compared to placebo or alendronate; as such, this agent carries an indication for treatment of osteoporosis in postmenopausal women at high risk of fracture, including those with multiple fragility fractures or those who cannot tolerate other osteoporosis therapies. It is not considered initial therapy at this time.
Romosozumab is given as two 105-mg subcutaneous injections each month for 12 months. Treatment effects are noted to decline after 12 months, therefore therapy beyond 12 months is not approved.51 Antiresorptive agents can be used after 12 months to preserve gains in BMD. Romosozumab was well-tolerated in trials.
Common side effects include injection site reactions and bone pain; rare cases of osteonecrosis of the jaw and atypical femoral fracture have been reported. Calcium and vitamin D should be corrected before treatment and maintained for the duration of therapy. Interestingly, an increased number of serious cardiovascular events occurred in the romosozumab group in preapproval trials.
There is a black box warning regarding an increased risk of myocardial infarction, stroke, and cardiovascular death. Romosozumab should not be initiated in patients who have had a heart attack or stroke in the previous year.53
Concomitant Use of Osteoporosis Therapy
A SERM and estrogen combination has been approved for osteoporosis prevention but not for treatment.64 The combination of two antiresorptive agents, such as estrogen replacement therapy and bisphosphonates, has shown only modest improvement in BMD and bone turnover but without additive fracture reduction.64,80
Similarly, adjunctive therapy consisting of antiresorptive and anabolic agents also has failed to add BMD benefit. Moreover, potential remains for the additive risk of deleterious side effects.81-86 Thus, no studies have demonstrated additional benefit for fracture reduction with combination osteoporosis therapy compared to a single agent.80-86 Additionally, combination therapies are not likely to be cost effective. Therefore, combination therapy with any osteoporosis therapy is not recommended for treatment of osteoporosis.19
Monitoring
Monitoring BMD change during therapy is important to identify a potential suboptimal response. However, no consensus guidelines are available on the optimal approach. One method is to repeat a DEXA measurement of the hip and/or spine after one to two years of treatment. More frequent testing may be considered in patients with presumed rapid bone loss, such as chronic glucocorticoid users.
If follow-up testing shows BMD is stable or improved, continue with less frequent monitoring thereafter.2,19 If BMD is decreased or a fracture occurs while receiving therapy, contributing factors should be reviewed. These include issues with medication efficacy, such as poor adherence, possible fear of side effects, inadequate gastrointestinal absorption, inadequate intake of calcium and vitamin D, or the development of a disease with adverse skeletal effects.
If these concerns are eliminated, the next step in management includes initiating therapy with an alternative route of administration (e.g., oral bisphosphonates to IV bisphosphonates or subcutaneous denosumab) or changing to a treatment with a different mode of action (switching from an antiresorptive to an anabolic agent such as a parathyroid hormone agent, especially at onset of fracture while on previous therapy).
Continuing with BMD measurement every one to two years helps to ensure the initial result was accurate; less frequent monitoring can be considered based on clinical circumstance.2,19 Routine monitoring of bone turnover markers during therapy is of unknown clinical utility and currently is not recommended, with the only exception being occurrence of fracture while receiving pharmacological therapy.2,19
Duration of Therapy
With long-term use of osteoporosis treatment, the benefits of BMD improvement and fracture reduction must be weighed with potential adverse effects. Improvements in BMD reach a plateau at three to four years, regardless of the drug used.2,19,35,37,38,48,52,54,56,62-64,70,73 Therefore, a drug holiday is recommended by some (although not by all) and remains controversial. Bisphosphonates accumulate in bone and may have persistent effects on BMD after therapy cessation; “bisphosphonate holidays” may be considered.
Patients who have low fracture risk, have stable BMD, and have no previous vertebral fractures may consider stopping oral bisphosphonates after five years or IV zoledronic acid after three years. However, patients who are at higher risk should receive a duration of 10 years of oral bisphosphonates or six years of IV zoledronic acid therapy. High-risk patients include those with a history of osteoporotic fracture before or during therapy, T-score below -3.5, increased fall risk, or frailty. The risk-benefit ratio of any osteoporosis treatment beyond 10 years is unknown.19
During a “bisphosphonate holiday,” no other treatment may be needed for low-risk patients (e.g., improvement in BMD or stable BMD without a fracture). Other agents, such as teriparatide or raloxifene, may be used for higher-risk patients during a “bisphosphonate holiday.”
The optimal duration of a “bisphosphonate holiday” is unknown but usually does not last longer than five years.2 It is theorized that based on binding affinity, it may be reasonable to schedule a longer “holiday” with zoledronic acid, followed by alendronate, and perhaps the shortest “holiday” with risedronate.42,87 Alternatively, planning to restart bisphosphonates after a three- to five-year “holiday” in women who showed BMD improvement during the initial use of bisphosphonates can be considered.
Recommendations regarding “bisphosphonate holidays” are less clear for ibandronate because cessation and resumption of therapy have not been evaluated fully. It may be prudent to restart bisphosphonate therapy if at any time a patient sustains a fracture or has significant and persistent bone loss of more than 5% on at least two DEXA measurements.
As stated earlier, other agents that result in a rapid decrease in BMD after therapy cessation, such as denosumab, calcitonin, and raloxifene, should not be stopped without a full evaluation of risks and benefits. Parathyroid hormone-related agents should not be used for more than two years because of the concern regarding the occurrence of osteogenic sarcoma. Romosozumab should be used for a total of 12 months per the package insert, followed by antiresorptive agents.
Conclusion
As osteoporosis rates continue to rise, vigilance with screening and treating affected patients is paramount. Primary care providers should be able to identify patients at risk for low BMD and osteoporosis and recommend appropriate prevention strategies. Timely screening should be performed and, based on results, an accurate diagnosis should be made. Primary care providers should be comfortable with varying osteoporosis treatment options and understand how and when to monitor and discontinue therapy.
Emily Beckett, PharmD, is with the University of Iowa College of Pharmacy, Iowa City; Broadlawns Medical Center, Des Moines, IA.
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Bones, as reservoirs of calcium and phosphorus, continuously remodel to maintain strength and function. However, suboptimal peak bone mass in young adulthood, excessive resorption of bone, or impaired bone formation during remodeling can result in osteoporosis. Among Caucasian adults ages 50 years and older in the United States, about 50% of women and 20% of men will experience an osteoporotic fracture in their remaining lifetime; however, fracture rates differ by ethnic/racial population and skeletal site. Annual fracture-related costs are expected to increase from $57 billion to more than $95 billion by 2040. Therefore, it is imperative that primary care providers address this challenge by implementing practices to screen patients for osteoporosis to prevent and/or treat the disorder and subsequent comorbidities.
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