Endocrinology Metabolism

Postmenopausal osteoporosis

Are You Sure the Patient Has Osteoporosis?

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.

Bone strength is a composite of bone density and bone quality and includes factors such as degree of mineralization, microdamage, collagen structure, trabecular connectivity, fatigue damage and macroarchitectural changes, eg. an increase in femoral neck length weakens bone.

In 1994, the World Health Organization (WHO) established an operational definition for osteoporosis based on bone mineral density (BMD), and this has become the standard definition over the years. The T-score compares an individual's BMD with the mean value for young normal individuals expressed in standard deviations (SD) and the Z-score compares the values to age-, sex- and gender-matched.

  • 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

Osteoporosis can also be diagnosed clinically with the occurrence of a fragility fracture.

Clinical Findings

Symptoms related to osteoporosis are not seen unless fractures are present. Significant height loss should alert one to the possibility of vertebral fractures, even if asymptomatic. However, some loss of height might be secondary to intervertebral disc space narrowing. Vertebral fractures can occur spontaneously or after minor trauma. The clinical course in an individual is unpredictable. They are usually associated with back pain, acute or chronic, localized or radicular and may interfere with ordinary activities. Deformity, prolonged disability and a change in self-image can occur.

On exam localized tenderness may be present and due either to the fracture, paravertebral muscle spasm or the development of an exaggerated thoracic kyphosis with consequent change in back alignment.

With multiple compression fractures and vertebral deformity there can be constriction of rib cage movement with shortness of breath and abdominal distension with early satiety.

Most nonvertebral fractures are caused by a fall. Hip fractures are the most serious complication of osteoporosis with mortality up to 20-25% in the year after the fracture. Recovery after a hip fracture can be prolonged with 50% of hip fracture patients who were independent before the fracture not regaining independence or requiring an assistive device for ambulation one year later.

One vertebral fracture increases the risk of another by 5-fold, and in those who have suffered 2 or more vertebral fractures, the risk is increased 12-fold.

Many patients after a wrist fracture suffer from pain, deformity, arthritis and limitation of function.

Risk factors for bone loss and fractures

Risk factors for low BMD in postmenopausal women:

  • advanced age

  • genetics (70-80% of bone structure is genetically determined)

  • low body weight (low body mass index)

  • low calcium and vitamin D intake

  • smoking

  • menopausal status

Risk factors for osteoporosis-related fractures:

  • advanced age

  • prior fragility fracture

  • low bone mineral density

  • low body weight

  • parental history of hip fracture

  • use of glucocorticoids

  • cigarette smoking

  • excessive alcohol consumption

  • secondary causes

Factors that increase the risk of falling and sustaining a fracture:

  • neurologic disorders

  • impaired vision

  • impaired hearing

  • fraility

  • sarcopenia

  • medications: sedatives, hypnotics, antihypertensives, narcotic analgesics

  • environmental factors: poor lighting, stairs, slippery floors, uneven surfaces, floor obstacles

For every standard deviation decrease in age-adjusted BMD, fracture risk increases about 2-fold. Site specific BMD measurements best predict fractures at that site. For example, hip BMD predicts hip fractures better than does BMD at other sites.

What Else Could the Patient Have?

Osteomalacia

Osteomalacia (a disorder of bone mineralization) with or without concomitant osteoporosis can cause low bone mass. It should always be considered as an associated factor in patients with osteoporosis. Osteomalacia in the postmenopausal population is most commonly due to vitamin D deficiency from little sunlight exposure, reduced intake or malabsorption.

Clinical manifestations of osteomalacia include muscle and joint aches, muscle weakness and balance disturbances.

Low levels of 25 OH vitamin D may be associated with secondary hyperparathyroidism with low serum calcium and phosphate and elevated parathyroid hormone (PTH) levels.

Plain radiographs of weight-bearing long bones may suggest pseudofractures, pathognomic for osteomalacia.

Secondary Causes of Osteoporosis

Endocrine/Metabolic

  • Primary Hyperparathyroidism

  • Hypercortisolism

  • Hyperthyroidism

  • Hypogonadism

  • Type 1 Diabetes Mellitus

  • Hypophosphatasia

  • Hypercalciuria

Nutritional

  • Alcoholism

  • Anorexia Nervosa

  • Calcium deficiency

  • Vitamin D deficiency

Gastrointestinal

  • Malabsorption:

    • Celiac disease

    • Crohn's disease

    • Gastric resection

    • Gastric bypass

  • Total parenteral nutrition

  • Chronic liver disease (eg. Primary biliary cirrhosis)

Medications

  • Aromatase inhibitors

  • Androgen-deprivation therapy

  • Chemotherapy/immunosuppressants

  • Depo Provera

  • Anticonvulsants: phenobarbital, phenytoin, valproate, carbamazepine, primidone

  • Glucocorticoids

  • Gonadotropin-releasing hormone agonists

  • Heparin

  • Lithium

  • Thyroid hormone-supraphysiologic doses

  • Proton pump inhibitors

  • Selective serotonin reuptake inhibitors

  • Thiazolidinediones

Collagen disorders

  • Ehlers-Danlos syndrome

  • Homocystinuria

  • Marfan syndrome

  • Osteogenesis imperfecta

Other

  • Ankylosing spondylitis

  • Immobilization

  • Chronic renal disease

  • Rheumatoid arthritis

  • Systemic mastocytosis

  • Multiple myeloma

  • Lymphoma, leukemia

  • Organ transplantation

  • Renal tubular acidosis

  • Thalassemia

Key Laboratory and Imaging Tests

Bone Density Measurements

BMD is the principal determinant of fracture risk and its measurement is often essential to management decisions. However, it should only be ordered if the results will affect clinical decision making.

BMD should be considered in postmenopausal women as follows:

  1. All women age 65 or older

  2. Younger postmenopausal women with history of fragility fracture (fracture or fall from standing height)

  3. Starting or continuing long-term glucocorticoid therapy

  4. Radiographic osteopenia

  5. Clinical risk factors for osteoporosis: thinness (body weight < 127 lbs or BMI < 21 kg/m2), spine or hip fracture in parent, cigarette smoking, alcohol intake of more than 3 units per day (one unit is 8 oz beer, 4 oz wine, 1 oz liquor

Dual-energy X-ray absorptiometry (DXA) measurements of the spine, hip and forearm are accurate and reproducible. The hip (total hip and femoral neck) and spine are generally measured and diagnostic criteria and therapeutic results have been validated for these sites and not for peripheral sites. The peripheral measurements can identify patients at increased fracture risk. The forearm, primarily 1/3 distal radius is useful when the spine is unreliable or primary hyperparathyroidism is present or suspected.

In some individuals, especially with advancing age, spine measurements may become inaccurate due to degenerative changes, sclerosis, scoliosis or fracture. The values then are artificially high and may give one a false sense that bone loss is less significant or the therapeutic intervention is working. The most reliable results are when the same instrument at the same bone density center is used.

Bone density is either reported as areal density (DXA) in grams of mineral per square centimeter, or volumetric density (quantitative CT) in milligrams per cubic centimeter. These values are then reported as T- or Z- scores. The T-score represents the number of SD from normal young adult mean values. The Z-score represents the number of SD from the normal mean value for age-, sex- and gender-matched control subjects. The T-score is used for the diagnosis of osteoporosis and a low Z-score may suggest secondary cause for osteoporosis.

In patients without a prior fracture, BMD is the single best predictor of future fractures. For every 1 SD decrease, fracture risk approximately doubles (1.6-2.6 fold). Although fractures are more likely to occur the lower the bone density, more than 50% of fragility fractures occur in patients with BMD in the low bone mass category.

When to repeat bone density testing

  • Bone loss may begin before the menopause. In the five years before and after cessation of menses, bone loss may average 1% a year. In some the rate is higher. Thereafter, the rate of bone loss slows.

  • In untreated postmenopausal women bone density testing should be repeated in 2-5 years.

  • In patients on treatment for osteoporosis, bone density testing should be repeated in 1-2 years. Many third-party insurers will pay for bone density testing yearly but medicare generally pays for every two years.

  • In patients who are on a drug-holiday, a follow-up bone density testing in 1-2 years is reasonable and helpful.

What indicates a significant change in BMD testing?

A value equal to or greater than the least significant change (LSC) is considered significant. The LSC should be established at each bone density center. Despite BMD values that might look to be changing, if they fall within the LSC they should be considered stable and within the precision of the instrument. BMD values should be used to assess changes and not the T-score.

Spine radiographs

Spine radiographs, either standard lateral thoracic and lumbar or vertebral fracture assessment (VFA) from DXA measurements can help identify vertebral fractures or deformities. This knowledge may alter therapeutic decisions. Patients with unexplained height loss, kyphosis or acute back pain should be considered for vertebral imaging.

Laboratory testing to assess for secondary causes of osteoporosis

  • Complete blood count: anemia. multiple myeloma, chronic illness

  • Serum calcium:

    • high - primary hyperparathyroidism

    • low - vitamin D deficiency, osteomalacia

  • Serum phosphorus:

    • high - renal failure

    • low - primary hyperparathyroidism, osteomalacia

  • Serum albumin: low. used to correct serum calcium, nutritional deficiencies

  • Serum liver enzymes: high. liver disease

  • Serum alkaline phosphatase: high. Paget's disease, osteomalacia, vitamin D deficiency, healing fracture, liver disease,

  • Serum creatinine: high. renal failure

  • Serum electrolytes: high CO2. acidosis

  • Serum 25 OH vitamin D: low. vitamin D deficiency, malabsorption

  • 24 hour urine calcium and creatinine: high urine calcium. hyperparathyroidism, renal calcium leak, high calcium intake, multiple myeloma, metastatic cancer, hyperthyroidism

  • Serum thyrotropin: low. hyperthyroidism

  • Serum PTH: high. primary or secondary hyperparathyroidism

  • Serum protein electrophoresis: M spike. multiple myeloma, monoclonal gammopathy of uncertain significance

Other Tests That May Prove Helpful Diagnostically

  • Tissue transglutaminase: high - celiac disease

  • Acid-base studies: abnormal - acidosis, renal tubular acidosis

  • Urine free cortisol, salivary cortisol: high - hypercortisolism

  • Serum tryptase: high - mastocytosis

  • Urine N-telopeptide, serum C-telopeptide elevated - increased fracture risk

Bone turnover markers

Bone turnover markers are useful for assessing skeletal function. Markers of osteoclastic bone resorption include urine N-telopeptide (NTx), serum C-telopeptide (CTx) and deoxypyridinoline. Markers of osteoblastic bone formation include bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide and osteocalcin. These markers cannot be used to diagnose osteoporosis, but increased markers of bone turnover are associated with increased fracture risk. They have varying degrees in predicting individual response to therapy, although rapid decreases may be seen within 2-3 months of initiating therapy. Their usefulness is limited because they vary from day to day, are affected by food intake and time of day and show assay variability.

Urine NTx should be obtained on a second void morning specimen before eating and serum CTx before eating. However, they may be an early indication of response to therapy. Elevated bone turnover resorption markers despite anti-resorptive therapy may indicate lack of response to therapy or non-compliance to taking the medication.

Management and Treatment of the Disease

Management and Treatment

The therapeutic approach to treating osteoporosis and preventing further bone loss involves two approaches:

1. Non-pharmacologic: calcium, vitamin D, nutrition, exercise, fall prevention

2. Pharmacologic: estrogen, raloxifene, calcitonin, bisphosphonates, teriparatide, denosumab

Non-pharmacologic therapy

1. Calcium

Adequate calcium is important across the age spectrum. For women over age 50, the recommended daily calcium is 1200 mg (diet plus supplements). The daily calcium intake declines with advancing age. The average calcium intake for postmenopausal women is around 600 mg. With advancing age, calcium intake decreases, intestinal calcium absorption decreases, vitamin D deficiency is common and 1,25 (OH)2 vitamin D, the active form of vitamin D decreases.

It is preferable to attain the appropriate amount of calcium from dietary sources, primarily dairy products and calcium-fortified foods. However this is often difficult. Dietary calcium is readily available, nutritious and better absorbed than calcium tablets.

There are many calcium supplements available as different calcium salts. The two most common are the calcium carbonate and calcium citrate preparations. The amount of elemental calcium in calcium carbonate is 40% and calcium citrate 21%. Thus, a 1250 mg tablet of calcium carbonate has 500 mg elemental calcium and a 750 mg tablet has 300 mg elemental calcium. It is important to know what the calcium preparation is and how many tablets, caplets or packets make up a serving size. This can be confusing to patients. Have them bring in their calcium, vitamin D and multivitamin preparations to review.

Calcium carbonate has the most calcium, thus requiring fewer tablets and is generally the least expensive. However, it may cause abdominal discomfort with bloating and constipation. It also requires gastric acid for absorption and is poorly absorbed if proton pump inhibitor therapy is given. It is better absorbed when taken with food.

Calcium citrate has less calcium per tablet, thus requiring more tablets and is often more expensive. However it is generally better absorbed and is not dependent on gastric acid and causes less gastrointestinal (GI) complaints.

No more that 500-600 mg of calcium should be given at one time. If higher doses are required, the doses should be split. For those unable to swallow tablets, chewable tablets and liquid calcium preparations are available.

Calcium can be considered a weak anti-resorptive agent. Studies have shown slight increases in BMD, but no reduction in fractures without vitamin D. A slight increase in urine calcium excretion may be seen with calcium supplements but not necessarily a significant increase in kidney stones. Patients with a known history of nephrolithiasis should be evaluated for the cause before calcium supplements are given.

2. Vitamin D

Vitamin D insufficiency and deficiency may be common in postmenopausal women especially in those living in northern latitudes. It is also common in institutionalized and home-bound persons.

Vitamin D is not widely available in foods except in fatty fish and those foods fortified with vitamin D such as milk, cereal and bread. Vitamin D can be produced naturally from precursors in the skin, but the conversion is blocked with sunscreen having a sun protection factor of 8 or higher.

The National Osteoporosis Foundation recommends a vitamin D intake of 800-1000 IU per day. The recent Institute of Medicine guidelines recommend a vitamin D intake of 600 IU for women age 51-70 and 800 IU for those over age 70. Many experts recommend levels in the 1000-2000 IU range and sometimes higher to maintain an adequate serum 25 OH vitamin D level. An upper limit of 4000 IU is suggested to be safe by the Institute of Medicine.

Vitamin D adequacy is assessed by measuring serum 25-OH vitamin D and not 1,25 (OH)2 vitamin D levels. The Institute of Medicine report suggests that a serum level of 20 ng/ml would protect 97.5% of the population against adverse skeletal outcome risks such as fracture. Many feel this is much too low and the minimal accepted level is in the 30 ng/ml range. Below this, parathyroid hormone levels increase and the fractional absorption of calcium decreases. They feel the best range for 25 OH vitamin D is 30-60 ng/ml although levels up to 100 ng/ml will unlikely cause problems.

Serum 25 OH vitamin D levels will rise roughly 1 ng/ml for every 100 IU per day of additional cholecalciferol (vitamin D3). It takes 3 months to achieve a new steady state after a vitamin D dose is changed. Most calcium and vitamin preparations add vitamin D. At high doses vitamin D3 (cholecalciferol) is approximately 30% more potent than vitamin D2 (ergocalciferol).

Sometimes with vitamin D deficiency, high-dose vitamin D2 50,000 IU weekly for 8-12 weeks is given. Other regimens suggest daily for 5-7 days or 2-3 times a week for several weeks. These regimens are then followed by vitamin D3 1000-2000 IU daily.

Vitamin D alone (700-800 IU) or with calcium supplements (1000 mg calcium) have been reported to reduce hip and nonvertebral fractures.

Vitamin D improves muscle strength and balance and reduces the risk of falling. All other reported non-skeletal beneficial effects of vitamin D are not proven.

3. Other nutrients and vitamins

Magnesium supplements have not been shown to increase BMD, reduce fracture risk or increase calcium absorption. Magnesium supplementation is appropriate in individuals with excessive losses, eg. GI diseases with malabsorption and with loop diuretics.

Low dose vitamin K (1 mg/day) may reduce bone loss but this needs to be confirmed. Vitamin K is contraindicated in persons on warfarin.

Adequate dietary protein intake should be achieved. Soy isoflavones (natural estrogens) have not been conclusively shown to increase BMD or reduce fracture risk.

Excessive alcohol should be avoided because of its detrimental effect in fracture risk due to increased propensity to fall, calcium and vitamin D deficiency and liver disease. Postmenopausal women should not exceed 7 units of alcohol a week. (1 unit equals 8 oz beer, 4 oz wine, 1 oz liquor).

Limit caffeine to 8-12 oz once or twice a day. This includes caffeinated beverages.

Cigarette smoking is a risk factor for bone loss, perhaps by increasing the metabolism of endogenous estrogen.

4. Exercise

Weight-bearing and strength-training exercises can produce small but significant increases in BMD, improve balance and muscle strength and reduce the risk of falls. Intensive exercises are not necessary and even mild ones such as walking 30-60 minutes are helpful. Jogging provides additional impact loading to the skeleton. Progressive resistance with machines are used in strength training programs but free weights or resistance bands can be used. The exercises should target specific muscle groups of the back, thigh and arm. Patients with severe osteoporosis should avoid high-impact exercises, trunk flexion or side-bending exercises or using heavy weights. Water aerobic exercises can help and gentle spinal extension exercises performed while seated in a chair can strengthen back extensor muscles.

A physical therapy consult may be helpful especially in those with severe osteoporosis and who have had fractures.

5. Fall prevention

The majority of osteoporotic fractures, especially non-vertebral are related to a fall. Fall prevention should be part of all osteoporotic management programs. An exercise program to improve balance and muscle strength reduces falls. Adjusting or discontinuing medications such as psychotropic drugs, narcotics, benzodiazepines, neuroleptics and antidepressants. Improve safety in the home by improving lighting, remove clutter and obstruction, avoid slippery floors, use nonskid mats, install grab bars in the bathroom and handrails on stairs. Hip protectors may help those prone to fall but compliance is poor.

Pharmacologic Therapy

Pharmacologic intervention should be considered in all patients with osteoporosis, have osteoporotic fractures or are at high risk for fracture.

Fracture Risk:

Fracture risk can be determined by combining BMD with clinical risk factors. In 2008 the World Health Organization released a Fracture Risk Assessment tool (FRAX). This is available at www.shef.ac.uk/FRAX and incorporates clinical risk factors and femoral neck BMD in determining fracture risk. It estimates the 10-year probability for hip fractures and major osteoporotic fractures for an untreated person. The clinical risk factors include age, body mass index, history of previous fractures, parental hip fractures, glucocorticoid therapy, current cigarette smoking, alcohol use, rheumatoid arthritis and secondary osteoporosis. Femoral neck bone density is used in the calculation.

Guidelines for treatment in postmenopausal women (National Osteoporosis Foundation)

  1. Hip or spine fracture.

  2. T-score -2.5 or below at the spine, femoral neck or total hp

  3. T-score between -1.0 and -2.5 and high 10 year risk for fracture using the US-adapted FRAX tool. Treat if the 10 year risk is 3% or more for hip fractures or 20% or more for major osteoporosis-related fractures

Bisphosphonates

For the treatment of postmenopausal osteoporosis the bisphosphonates are the first-line therapy. They increase bone density and reduce the risk for spine, hip and non-vertebral fractures. The bisphosphonates are generally safe and well tolerated. They have been clinically used to treat osteoporosis since alendronate was first approved in 1995.

The bisphosphonates are synthetic analogues of pyrophosphate that bind to the hydroxyapatite in bone and inhibit osteoclastic bone resorption.

The oral bisphosphonates are poorly absorbed, usually less than 1%. They should be taken on an empty stomach with 8 oz of plain water. Patients should remain upright for 30 minutes (60 minutes for ibandronate) and avoid eating, drinking (except plain water) or taking other medications during that time.

Patients should not receive bisphosphonates if they show hypersensitivity to them or are hypocalcemic until this is corrected. It is also not recommended for patients with creatinine clearance <35 mL/min.

Oral bisphosphonates should be used with caution in patients with upper GI problems (eg reflux). They should not be given to patients with Barrett's esophagus, esophageal varices or to those who have abnormalities that delay transit of the tablet (eg. achalasia or strictures).

Intravenous bisphosphonates (ibandronate and zoledronic acid) can cause acute-phase symptoms in up to 30-35% of patients receiving the first dose. These reactions include fever, muscle and joint pains, flu-like symptoms and headache. These are transient, generally occur within the first 24 hours and last 24-72 hours (occasionally longer). These symptoms are less likely if an oral bisphosphonate had previously been given and the incidence of these acute-phase symptoms is markedly reduced with subsequent infusions.

Some patients given bisphosphonates may develop muscle, joint and bone pains at any point during treatment.

Osteonecrosis of the jaw (ONJ) occurs rarely with bisphosphonate therapy for osteoporosis. ONJ is the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a health care professional. It is seen primarily in cancer patients receiving intravenous bisphosphonates in doses much higher (10-12 fold) than given to treat osteoporosis. Risk factors include invasive dental procedures, poor dental hygiene and other dental problems. Patients should take care of major dental problems before starting bisphosphonate therapy and practice good dental hygiene with regular follow-up.

Atypical femur fractures of the subtrochanteric region and femoral shaft with bisphosphonate use have been reported. Although uncommon, they are more likely with longer duration of therapy. They may be bilateral. The mechanism is not clear but may be related to over-suppression of bone turnover, not allowing for repair of microfractures. Patients sometimes complain of leg pain or an aching sensation prior to the fracture and this may be related to an unrecognized stress fracture.

Alendronate

Alendronate (Fosamax), now also in generic form, is approved by the Food and Drug Administration (FDA) for the following:

  1. Prevention of postmenopausal osteoporosis: 5 mg PO daily, 35 mg PO weekly

  2. Treatment of postmenopausal osteoporosis: 10 mg PO daily, 70 mg PO weekly

  3. Treatment of glucocorticoid-induced osteoporosis in men and estrogen-replete women: 5 mg PO daily

  4. Treatment of glucocorticoid-induced osteoporosis in estrogen-deficient women: 10 mg PO daily

  5. Treatment of osteoporosis in men: 10 mg PO daily, 70 mg PO weekly

Alendronate increases BMD at the spine and hip and prevents bone loss at the forearm. It reduces the risk of fracture of the spine, hip and nonvertebral sites.

Most common side effects are upper GI with heartburn, indigestion and swallowing difficulties. In one report, after discontinuation of alendronate at 5 years, there is a slow decline in bone density but at 10 years the BMD is still higher than baseline and the fracture incidence similar to 10 years of treatment except for a higher incidence of clinical vertebral fractures. However, women with severe osteoporosis were excluded from the study.

Risedronate

Risedronate (Actonel) is approved by the FDA for the following:

  1. Prevention of postmenopausal osteoporosis: 5 mg PO daily, 35 mg PO weekly, 150 mg PO monthly

  2. Treatment of postmenopausal osteoporosis: 5 mg PO daily, 35 mg PO weekly, 150 mg PO monthly

  3. Prevention of glucocorticoid-induced osteoporosis: 5 mg PO daily

  4. Treatment of glucocorticoid-induced osteoporosis: 5 mg PO daily

  5. Treatment of osteoporosis in men: 35 mg PO weekly, 150 mg PO monthly

Risedronate increases BMD at the spine and hip and prevents bone loss at the forearm. It reduces the risk of fractures of the spine, hip and nonvertebral sites.

After discontinuing risedronate slow bone loss may occur and after 1 year bone turnover markers return towards baseline.

The most common side effects are of the upper GI system.

Ibandronate

Ibandronate (Boniva) is approved by the FDA for the following:

  1. Prevention of postmenopausal osteoporosis: 2.5 mg PO daily, 150 mg PO monthly

  2. Treatment of postmenopausal osteoporosis: 2.5 mg PO daily, 150 mg PO monthly, 3 mg IV every 3 months

Ibandronate reduces the risk of spine fractures in women with postmenopausal osteoporosis but has not shown a reduction in nonvertebral or hip fractures in prospective studies. In a post-hoc analysis of patients with femoral neck T-score below -3.0, there was a 69% reduction in non-vertebral fracture risk.

Ibandronate increases BMD at the spine and hip and prevents bone loss at the forearm.

Side effects generally involve the upper GI tract.

Zoledronic acid

Zoledronic acid (Reclast) is approved by the FDA for the following:

  1. Prevention of postmenopausal osteoporosis: 5 mg IV every other year

  2. Treatment of postmenopausal osteoporosis: 5 mg IV once yearly

  3. Prevention of glucocorticoid-induced osteoporosis: 5 mg IV once yearly

  4. Treatment of glucocorticoid-induced osteoporosis: 5 mg IV once yearly

  5. Treatment of osteoporosis in men: 5 mg IV once yearly

  6. After surgical repair of hip fracture: 5 mg IV once yearly

Zoledronic acid reduces the risk of spine, hip and non-vertebral fractures. It also reduces the rate of new clinical fractures in patients treated with surgical repair of a hip fracture and reduces mortality in these hip fracture patients. Zoledronic acid increases BMD at the spine and hip.

Acute-phase symptoms (fever, muscle and joint aches, flu-like symptoms) have been reported in 32% of subjects after the first infusion; 7% after the second and 3% after the third. Patients should be adequately hydrated, may take acetaminophen or a non-steroidal anti-inflammatory agent and should continue calcium and vitamin D. Before the infusion serum calcium and creatinine should be checked.

The potential problem of ONJ has been reported primarily in patients who receive intravenous bisphosphonates for skeletal metastases in cancer patients at a dose much higher than given for osteoporosis.

Raloxifene

Raloxifene (Evista) is a selective estrogen receptor modulator (SERM) which acts on different tissues as an estrogen-agonist or antagonist. Raloxifene is approved by the FDA for the prevention and treatment of postmenopausal osteoporosis as well as for the reduction of risk of invasive breast cancer in women with postmenopausal osteoporosis or at high risk for breast cancer. The dose is 60 mg PO daily and can be taken at any time of the day without regard to meals.

Raloxifene reduces the risk of fracture of the spine in women with postmenopausal osteoporosis but not hip or nonvertebral fractures. It increases BMD in the spine and hip. Side effects include hot flashes, night sweats, muscle and joint aches and leg cramps. There is a 3-fold increase in venous thromboembolic disease, similar to that seen with estrogen.

There are no beneficial or adverse cardiovascular effects. There also is no increase in cerebrovascular events although in a large study there was an overall increase in fatal strokes.

Safety has been determined for up to 8 years. After stopping Raloxifene the beneficial effects are lost in 1-2 years.

Teriparatide

Teriparatide (Forteo) is recombinant human PTH (1-34) fragment and is the only anabolic agent available to treat postmenopausal osteoporosis. It is approved by the FDA for the following:

  1. Treatment of postmenopausal osteoporosis: 20 micrograms SQ daily

  2. Treatment of glucocorticoid-induced osteoporosis: 20 micrograms SQ daily

  3. Treatment of osteoporosis in men: 20 micrograms SQ daily

Teriparatide reduces vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. It increases spine BMD but has little effect on hip or forearm density.

Side effects are mild and transient and include nausea, orthostatic hypotension, leg cramps and a slight increase in serum calcium for several hours after the injection.

There is a black box warning because in rats given doses of teriparatide up to 60-fold what is given for osteoporosis in humans, there was an increase in osteosarcoma. This has not been observed in humans given teriparatide. The rat skeleton differs from humans. It grows for its entire lifespan (rather than remodel in humans) and if teriparatide is administered beginning at 2 weeks- 6 months of age, it then ends up being given for over 75% of the rat lifespan of 2 years, compared to 2-3% for humans. Because of this finding, teriparatide is contraindicated in patients at increased baseline risk for osteosarcoma; Paget's disease of bone, open epiphysis, history of radiation involving the skeleton or an unexplained elevation of alkaline phosphatase.

Because of the rat data, teriparatide is not recommended for more than 2 years. It has been available for treatment for over 10 years.

After stopping teriparatide, BMD declines in the following year, but fracture risk reduction can continue. After treatment with teriparatide, the administration of an anti-resorptive agent, such as the bisphosphonates may help prevent bone loss and maintain gains.

Calcitonin

Calcitonin injectable and nasal spray is approved by the FDA for the treatment of postmenopausal osteoporosis. The injectable calcitonin is given as 100 IU daily SQ or IM. The nasal spray (Miacalcin, Fortical) as 200 IU daily.

Nasal spray salmon calcitonin reduces the risk of vertebral fractures but not hip or nonvertebral fractures. No fracture reduction has been shown with the injectable calcitonin.

Calcitonin produces a small increase in spine BMD but not other sites.

Bone loss occurs rapidly after discontinuation.

Denosumab

Denosumab (Prolia) is a human monoclonal antibody against RANKL (RANK ligand). This reduces the differentiation of precursor cells into mature osteoclasts and decreases function and survival of activated osteoclasts.

Denosumab is approved by the FDA for the following:

  1. Treatment of postmenopausal osteoporosis at high risk for fracture: 60 mg SQ every 6 months.

Denosumab reduces spine, hip and nonvertebral fractures. It increases BMD at the spine, hip and forearm.

Side effects include a small increase in serious infections such as skin infections which did not increase with continued use. ONJ has been reported primarily when denosumab was given to patients with cancer in higher doses than used for osteoporosis.

After discontinuation, BMD decreased to baseline and bone turnover markers increased by 12 months.

It is not affected by renal function and can be given to patients with reduced renal function.

Estrogen/hormone replacement therapy

Estrogen is approved for the prevention of osteoporosis. It is not approved for treatment. The major reason to give estrogen is for the treatment of menopausal symptoms.

Many different estrogen formulations are available. If the uterus is intact then a progestin should be given otherwise unopposed estrogen is associated with an increased risk of endometrial hyperplasia and cancer.

Conjugated equine estrogen has been shown to reduce the risk of spine, nonvertebral and hip fractures. Estrogen also increases BMD in the spine, hip and forearm.

There is significant controversy regarding side effects of hormone replacement therapy. In the Women's Health Initiative (WHI) a combination of estrogen and progestin produced an increased risk of breast cancer, cardiovascular events, thromboembolic and cerebrovascular events. In the WHI estrogen only trial there was no increase of risk in cardiovascular events or breast cancer.

Estrogen therapy increases the risk of cholelithiasis, fluid retention, headaches and a 3-fold increase in thromboembolic events.

Benefit persists only as long as treatment is continued and accelerated bone loss occurs as soon as treatment is stopped.

What is a nonresponder?

A significant decrease in BMD (greater that the least significant change) or a new fracture may be considered a nonresponder. However, these patients may have had greater bone loss or more fractures had they not received treatment, and thus may have shown some benefit from treatment. In these two settings, an assessment for compliance to treatment, evaluation for secondary causes of bone loss and reconsideration of changing treatment should be done.

If on an oral agent and there is a question of problems with absorption and one wants to continue using a bisphosphonate, then switch to an intravenous bisphosphonate. Parenteral denosumab can also be used. If on raloxifene consider switching to a bisphosphonate. Denosumab, or teriparatide can also be used if BMD is very low. If on a bisphosphonate, consider changing to an anabolic agent, teriparatide.

How long to treat?

There is no consensus, nor any consistent data about the duration of treatment or when to reinstitute therapy after a drug-holiday. The idea behind a drug-holiday is that drugs such as the bisphosphonates are retained in the skeleton for months to years and by giving a holiday you will still see the beneficial effect but lessen the potential for some of the adverse effects seen with long-term therapy.

It is reasonable to consider for those with mild to moderate osteoporosis without a fracture to take a drug-holiday after 5 years of treatment and reconsider starting again in several years when there is evidence for a decline in BMD or a new fracture.

In those with severe osteoporosis and fractures a holiday after 10 years of treatment may be considered and restarting therapy in 1-2 years or when there is evidence of a decline in BMD or a new fracture.

During the drug-holiday, consideration should be given to using an agent from another class.

What’s the Evidence?/References

Watts, NB, Bilezikian, JP, Camacho, PM, Greenspan, SL, Harris, ST. "American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis". Endocrine Practice. vol. 16. 2010. pp. 1-37.

(Detailed and extensive review with a large reference list.)

"Management of osteoporosis in Postmenopausal Women: 2010 Position Statement of the North American Menopause Society". Menopause. vol. 17. 2010. pp. 25-54.

(Update of previous NAMS position statement from 2006. Detailed and extensive review with a large reference list.)

"The 2012 hormone therapy position statement of The North American Menopause Society". Menopause. vol. 19. 2012. pp. 257-271.

(Reviews the effect of hormone therapy on many aspects of women’s health).

Brauer, CA, Coca-Perraillon, M, Cutler, DM, Rosen, AB. "Incidence and mortality of hip fractures in the United States". JAMA. vol. 302. 2009. pp. 1573-9.

(In the United States, hip fracture rates and subsequent mortality among persons 65 years and older are declining.)

Tang, BMP, Eslick, GD, Nowson, C, Smith, C, Bensoussan, A. "Use of calcium or calcium in combination with vitamin D supplements to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis". Lancet. vol. 370. 2007. pp. 657-66.

(Meta-analysis of 17 trials suggested that with calcium doses of 1200 mg and vitamin D of at least 800 IU there is a reduced fracture rate and an increase in bone mineral density.)

Ross, AC, Manson, JE, Abrams, SA, Aloia, JF, Brannon, PM. "A The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know". J Clin Endocrinol Metab. vol. 96. 2011. pp. 53-8.

(A summary with rationale behind the recent IOM report.)

Rosen, CJ. "Vitamin D insufficiency". N Engl J Med. vol. 364. 2011. pp. 248-54.

(A nice discussion of our understanding and uncertainties about vitamin D levels and supplementation.)

Khosla, S, Burr, D, Cauley, J. "Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research". J Bone Miner Res. vol. 22. 2007. pp. 1479-91.

(Discussion with definition, risk factors and clinical implications.)

Shane, E, Burr, D, Eberling, PR, Abrahamsen, B, Adlet, RA. "Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research". J Bone Miner Res. vol. 25. 2010. pp. 2267-94.

(Detailed discussion about atypical femoral fractures including possible association with long-term bisphosphonates, mechanisms, clinical presentation and need for further information.)

Black, DM, Schwartz, AV, Ensrud, KE, Cauley, JA, Levis, S. "Effects of continuing or stopping alendronate after 5 years of treatment. The Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial". JAMA. vol. 296. 2006. pp. 2927-38.

(Discontinuing alendronate after 5 years showed a moderate decline in BMD and gradual rise in bone turnover markers but no higher fracture risk other than for clinical vertebral fractures compared to those who continued alendronate for 10 years.)

Watts, NB, Diab, DL. "Long-term use of bisphosphonates in osteoporosis". J Clin Endocrinol Metab. vol. 95. 2010. pp. 1555-65.

(They recommend a drug-holiday after 5-10 years of treatment depending on fracture risk. Low-risk patients might remain off as long as BMD is stable and no fractures occur. Higher risk patients start back on treatment after 1-2 year holiday.)

Whitaker, M, Guo, J, Kehow, T, Benson, G. "Bisphosphonates for osteoporosis- Where do we go from here". N Engl J Med. vol. 366. 2012. pp. 2048-2051.

(The FDA reviewed long-term bisphosphonate efficacy and safety. They suggested labeling update but no regulatory restriction on duration of use.)

Black, DM, Bauer, DC, Schwartz, AV, Cummings, SR, Rosen, CJ. "Continuing bisphosphonate treatment for osteoporosis- For whom and for how long". N Engl J Med. vol. 366. 2012. pp. 2051-2053.

(Suggest guidelines for discontinuing or continuing bisphosphonates after 3-5 years of treatment.)

Weinstein, RS. "Glucocorticoid-induced bone disease". N Engl J Med. vol. 365. 2011. pp. 62-70.

(Review of the approach and treatment of this common clinical problem.)

Lobo, RA. "Where are we 10 years after the Women’s health Initiative". J Clin Endocrinol Metab. vol. 98. pp. 20-1780.

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