Endocrine abnormalities
Cushing’s syndrome, hyperthyroidism, hypogonadism
hyperparathyroidism, hypercalciuria, hyperprolactinemia, Panhypopituitarism, diabetes, androgen insensitivity
Hematological disorders
Multiple myeloma, leukemia, lymphoma, systemic mastocytosis, hemophilia, thalassemia, monoclonal gammopathies
Rheumatologic
Rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and other systemic inflammatory diseases
Gastrointestinal disorders
Gastric bypass, gastrectomy, IBD, primary biliary cirrhosis, celiac disease, pancreatitis
Renal
Renal failure, renal tubular acidosis
Pulmonary
Chronic respiratory diseases
Neurologic diseases
Epilepsy, multiple sclerosis, parkinsonism, muscular dystrophy, stroke, spinal cord injury
Genetic disease
Glycogen storage diseases, hemochromatosis homocystinuria, porphyria, Menke syndrome, Riley-Day syndrome, cystic fibrosis, homocystinuria, hypophosphatemia, Gaucher’s disease
Osteogenesis imperfecta, Ehlers-Danlos syndrome, Marfan syndrome
High-risk medications
Long-term steroids (≥5 mg/day prednisone or equivalent for ≥3 months), phenytoin and carbamazepine [6], heparin, gonadotropin-releasing hormone agonists, lithium, aromatase inhibitors, aluminum (in antacids), cancer chemotherapeutic drugs, depomedroxyprogesterone [7], proton pump inhibitors, tamoxifen (premenopausal use) [8], thiazolidinediones, thyroid hormones (in excess)
Risk Factors for Osteoporosis
Non-modifiable risk factors of low bone mass | Modifiable risk factors of low bone mass |
|---|---|
Advancing age | Low calcium or vitamin D intake |
Race (white/Asian) | Sedentary lifestyle |
Female gender | Cigarette smoking |
Early menopause and late menarche | Lack of sunlight exposure |
Slender build (<127 pounds) | Estrogen deficiency |
Family history of hip fragility fracture | Alcohol excess or caffeine excess |
Dementia | Glucocorticoid therapy |
Fracture after the age of 50 years | |
Neurologic disorder | |
Inability to stand from a chair without using arms | |
Self-evaluation of health as fair to poor |
Osteoporosis in Men [9]
This has become a significant health concern. Fractures in men increase dramatically after age 70, typically beginning 5–10 years later in life than women. The incidence of hip fracture is one-third to one-half of that in women. Hip and spine fractures are more prevalent in men older than 70 years. Men are less likely than women to be treated with antiresorptive therapy after a hip fracture. This is likely multifactorial in etiology, but provider ignorance and clinical inertia appears contributory. Severe hypogonadism from androgen deprivation therapy for prostate cancer is common in elderly men, as is hypogonadism, alcohol abuse, smoking, gastrointestinal and hepatic disorders and malabsorption.
Clinical Features of Osteoporosis
Osteoporosis has no clinical manifestations until a patient experiences a fracture.
Loss of height (>1.5 inch), localized spinal pain (indicative of fracture), accentuated kyphosis (Dowager’s hump), or vertebral compression fracture on a chest radiograph may be seen. Almost all non–spine-related fractures occur as a result of trauma and have the acute signs and symptoms of a fracture. However osteoporotic vertebral fractures frequently do not result from overt trauma, leading to a delayed diagnosis.
Evaluation of Osteopenia/Osteoporosis
Basic lab evaluation |
Serum creatinine, albumin, calcium, phosphorous, alkaline phosphatase levels |
Serum 25-hydroxy vitamin D level |
Serum thyroid stimulating hormone |
Serum testosterone levels in men |
Celiac disease antibody testing (if white with symptoms or low 25-OH vitamin D level) |
24-hour urinary calcium level |
Additional testing if the basic evaluation does not elucidate the cause |
Serum protein electrophoresis if over the age of 50 years with undiagnosed anemia |
Serum parathyroid hormone level |
Bone biopsy under calcified sections with double tetracycline label |
Serum biochemical markers of bone turnover |
Urinary free cortisol |
Methods of Evaluating Bone Mineral Density
Radiographs
Osteopenia/Osteoporosis on radiographs in the absence of fracture is a very subjective observation, and this terminology is frequently misused. Conventional X-ray techniques are insensitive in the evaluation of bone density at any skeletal site because 30–40% bone must be lost before it is radiologically evident.
Single Photon Absorptiometry of the Radius or Heel
This involves determining the mineral content of bone by measuring the absorption of a monochromatic, low energy photon beam, produced by a radioactive source (iodine-125 or americium-241). However, disadvantages include the fact that the object of study might consist of only two materials with different absorption coefficients. Also, the radioactive source needs to be replaced after a certain period.
Quantitative CT Scan (QCT) of the Lumbar Spine
QCT is a true bone density measured in g/cm3, and it can analyze the trabecular and cortical compartments of bone unlike DEXA. Unfortunately, the disadvantages include lower precision, a higher dose of ionizing radiation, lesser availability and complex scanner operation when compared to DEXA. Additionally, most large epidemiological osteoporosis studies with fracture endpoints have not used QCT measurements.
Calcaneal Ultrasound (Quantitative Ultrasound/QUS)
QUS employs high-frequency sound waves to determine bone density, and QUS correlates with the BMD measured by DEXA. QUS could discriminate subjects with and without a fracture history and predict risk for future fracture. Therefore, QUS is convenient and provides information on bone microarchitecture as well as BMD. However as numerous QUS devices have been developed by many manufactures, each with its own designed logarithm for the calculation and interpretation of QUS indices, inter-device comparison of the results of bone health assessment is not possible. Furthermore, the precision of QUS is reported to be poorer compared to DEXA.
Dual Energy X-Ray Absorptiometry (DEXA)
This is currently the gold standard for measuring bone mineral density and determining whether someone has normal/osteopenic or osteoporotic bone. Its advantages include a low radiation exposure of 1–5 micro Sieverts and short procedure time of less than 20 minutes. Also, it does not require a complex scanner operation and has lower cost compared with QCT.
The disadvantages of DEXA include its inability to capture three-dimensional bone microarchitecture; the bone mineral density values obtained with dual X-ray absorptiometry do not represent true volumetric bone mineral density, but a projected areal bone mineral density and DEXA cannot distinguish between increased bone mineral density values arising from thicker bones and those arising from increased tissue mineral density (such as from osteophytes). Hence DEXA may give falsely high BMD values in those with bone-forming pathologies such as osteoarthritis and spondyloarthropathies and in patients who have had orthopedic or neurologic surgery. DEXA scans can be distorted by aortic calcification, soft-tissue calcification and other artifacts in older individuals.
T-score: the number of SD (standard deviations) the patient is below or above the mean value for young (30 years old) normal subjects (peak bone mass) but is used only for postmenopausal women and men >50 years of age. This is a good predictor of the fracture risk.
Z-score: defines how the bone mineral density (BMD) compares to age matched controls and is used for premenopausal women and men <50 years old.
Absolute BMD: This is expressed in g/cm2. This is the value needed to calculate changes in BMD, and whether those changes are significant.
The World Health Organization Criteria for Osteoporosis [11]
Diagnostic criteria | Classification |
|---|---|
T ≥ −1 | Normal |
T = −1 to −2.5 | Osteopenia(low bone mass) |
T ≥ −2.5 | Osteoporosis |
Osteoporosis + fracture | Severe or established osteoporosis |
For premenopausal women and men <50 years of age
A Z-score of < −2.0 is interpreted as “bone density which is below the expected range for age.”
A Z-score of > −2.0 is interpreted as “bone density which is within the expected range for age.”
Because very small changes in a patient’s bone mass may be significant, and the BMD is reported to the thousandth decimal place, the BMD is used to determine whether a patient’s bone density has significantly changed when compared with a prior DEXA.
To assess response to therapy, the follow-up DXAs must be performed on the same machine as the prior scan or on a machine with which it was cross calibrated, to avoid or minimize intermachine variability. The Least Significant Change (standard error) is the amount that is considered a statistically significant difference, when compared with a prior timepoint. The National Osteoporosis Foundation recommends treatment for all people who have a lumbar spine, hip or femoral neck T-score of −2.5 or lower. For people who have a bone density between −1 and −2.5, the National Osteoporosis Foundation recommends performing a Fracture Risk Assessment (FRAX), which provides a 10-year risk of a hip fracture or a major osteoporotic fracture. At least two different locations must be tested: spine, right hip, left hip or nondominant mid shaft radius (especially if the patient has a cortical bone disorder such as hyperparathyroidism). Additionally, the spine measurement must contain at least two contiguous vertebrae. Because osteoporosis is a systemic disease, the lowest T score found determines the patient’s single diagnosis.
Clinical Indications for Measuring a Patient’s Bone Mineral Density
- 1.
All postmenopausal women <65 years who have one or more additional risk factors for osteoporosis (besides menopause)
- 2.
All women >65 years and men >70 years regardless of additional risk factors
- 3.
Adults with bone fragility fractures
- 4.
Adults with a condition associated with low bone mass or bone los
- 5.
Anyone being considered for therapy for osteoporosis
- 6.
Anyone being treated with bone anti-osteoporotic therapy to monitor treatment effect
- 7.
Anyone not receiving therapy in whom evidence of bone loss would lead to treatment
Fracture Risk Assessment (FRAX) https://www.shef.ac.uk/FRAX/tool [2]
- 1.
Age
- 2.
Sex
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Weight
- 4.
Height
- 5.
Previous fragility fracture
- 6.
Parental hip fracture
- 7.
Current smoking
- 8.
Current glucocorticoid use (≥5 mg prednisone for 3 months or more)
- 9.
Rheumatoid arthritis
- 10.
Secondary causes of osteoporosis, i.e., myeloproliferative disorders, chronic kidney disease, chronic liver disease, etc.
- 11.
Alcohol intake of 3 or more units/day (a unit of alcohol is equivalent to a glass of beer [285 mL], an ounce [30 mL] of spirits, or a medium-sized glass of wine [120 mL])
These risk factors are added to the femoral neck BMD in the FRAX equation to calculate the 10-year fracture risk. In the United States, either a 10-year risk of hip fracture of 3% or more or a major osteoporotic fracture of 20% or more is the threshold to recommend treatment. The fracture risk threshold for treatment is individualized by country, so it is important to enter the country in which the patient resides into the formula.
Treatment of Low Bone Mineral Density, Osteopenia, and Osteoporosis
The decision to initiate a bone-active agent for those with low bone mass is based on the patient’s risk stratification using the WHO FRAX tool, the lowest T-score value, and history of a fragility fracture.
Low risk: FRAX 10-year risk for a major osteoporotic fracture of <10%
Medium risk: FRAX 10-year risk of 10–20%
High risk: FRAX 10-year risk >20%, or a T-score below −2.5 at any site, independently or along with a history of a previous fragility fracture
Non-pharmacologic Interventions to Prevent Low Bone Mass or Fractures
Physical therapy—structured weight bearing exercise programs and gait training to improve coordination.
Interventions to prevent falls and resulting fractures.
Maintaining ideal body weight (there is no evidence that interventions aimed at gaining or losing weight in thin and obese persons, respectively, can reduce fracture risk).
Discontinue tobacco and excessive alcohol use.
Address modifiable risk factors including polypharmacy and environmental hazards.
Hip protectors, walking aids, safety aids at home (home safety check).
Pharmacologic Interventions
Daily calcium intake | Daily vitamin D intake | |
|---|---|---|
Women <50 years | 1000 mg | 400–800 IU |
Women >50 years | 1200 mg | 800–1000 IU |
Men 51–70 years | 1000 mg | 800–1000 IU |
Men >71 years | 1200 mg | 800–1000 IU |
In addition to calcium and vitamin D, pharmacological interventions are broadly divided into two categories, based on their net result as anti-resorptive and anabolic agents. Anabolic agents stimulate bone formation thereby increasing BMD-Teriparatide (Forteo). Strontium ranelate is not approved by the FDA. Anti-resorptive therapies (bisphosphonates, estrogen and selective estrogen receptor modulators, denosumab) reduce bone resorption thereby preserving bone mineral density (BMD).
Bisphosphonates
Alendronate, risedronate and ibandronate are oral formulations. Zoledronic acid, ibandronate and pamidronate are intravenous formulations. Although it was the first bisphosphonate used for osteoporosis, etidronate is not FDA approved for osteoporosis in the United States. Pamidronate is also not specifically approved for osteoporosis by the FDA. Oral bisphosphonates are poorly absorbed from GI tract and carry a risk of esophagitis. Weekly, monthly and yearly dosing improve patient compliance. Rare risks include atypical femur fractures and osteonecrosis of the jaw. Due to the potential of atypical femur fractures, many authorities recommend a two-year drug holiday after 5 years for oral bisphosphonates and after 3–5 years for zoledronic acid.
Contraindications to bisphosphonates include pregnancy, chronic kidney disease stage 4 or 5, low serum calcium (<8.5 mg/dl in the presence of a normal albumin), osteomalacia, vitamin D deficiency (until it is corrected), pre-existing esophageal conditions such as Barret’s esophagus, and patients who cannot stay upright for an hour, after taking the oral medication. A 25(OH) vitamin D level > 40 ng/ml has been associated with a more favorable response to bisphosphonate therapy [13].
After ingesting an oral bisphosphonate, the patient should be instructed to consume a tall glass of plain water and maintain an upright posture for 30 minutes. The side effects of nausea, dyspepsia, abdominal pain and gastritis are not significantly different between alendronate, risedronate or ibandronate and placebo.
Side effects of bisphosphonates include esophagitis (oral bisphosphonates), musculoskeletal pain (both oral and IV forms), an acute phase reaction consisting of fever, myalgia, and arthralgia for IV bisphosphonates, hypocalcemia for IV bisphosphonates, esophageal cancer which could be secondary to nonadherence to prescribing directions and resulting esophagitis, rare osteonecrosis of the jaw, and sub trochanteric fractures (the association of which have been questioned).
Denosumab
A monoclonal antibody which binds to and prevents RANKL from binding to RANK. It inhibits osteoclast formation, function and survival. Can be used in patients with renal dysfunction but not in hypocalcemia. The dosage is 60 mg subcutaneous every 6 months. Side effects reported in clinical trials include infections of the skin, GI tract, urinary system, ear, endocarditis [14] musculoskeletal pain and rash.
Teriparatide
Stimulates net bone formation when given subcutaneous. Its side effects include nausea, dizziness, headaches, muscle cramps, and hypercalcemia. Teriparatide is approved by the US Food and Drug Administration (FDA) to treat men and women with osteoporosis for up to 2 years. It is administered 20 mcg subcutaneous daily. Based on the first 7 years of the Osteosarcoma Surveillance Study (a 15-year study), there does not appear to be a causal association between teriparatide treatment and osteosarcoma in humans [15].
Calcitonin
Calcitonin prevents bone resorption and is administered intranasally or subcutaneous. Calcitonin at doses of 200 IU/ day stabilizes and may produce a short-term increase in bone density at the lumbar spine. However, the effect on nonvertebral fractures was not significant. But calcitonin diminishes bone pain in osteoporotic vertebral fractures; thus, its niche appears to be decrease pain in acute osteoporotic fractures.
FDA-Approved Agents for Osteoporosis
- A.
Anti-resorptive agents that lower the risk of spine, hip and non-vertebral fractures (first line agents)
- 1.
Alendronate (Fosamax)
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