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Dx Osteoporosis Treatments: Read more...


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Consensus
BreastCancer.org reports Only post-menopausal women receiving intravenous bisphosphonates showed statistical reduction in recurrent bone fracture (and recurrent breast cancer) although the number of individual helped/ per cost is still in question. Pre-menopausal women did not show significant improvement. All bisphosphonates increase the risk of atypical fractures and osteonecrosis of the jaw although the statistics are approximately 1 in 500 individuals.
The JAMA study found subsequent bone density measurements do not predict fracture. While bisphosphonates are considered standard of care, their association with rare atypical fractures, increased risk of subtrochanteric or femoral shaft fracture, and esophageal cancer are troublesome.

The National Osteoprosis Foundation stated in JAMA 2015 April 15; 313(14) 1467-8 "There are no controlled studies that have shown that screening for osteoporosis reduces fractures or fracture-related morbidity or mortality. No studies imply screening is of benefit for men.

*[Editor] Osteoporosis is a completely preventable disease, in most cases.
The key to prevention might well be maintaining levels of testosterone in men, testosterone and estrogen in women, and lowering SHBG to young adult levels starting before 40-60 years of age.



*[Editor]
"More than 1,000,000 have Listened to the i-Doctor Podcasts!"
Mary is now 86 years old. [Photograph at 80] Her bone density is that of an 18 year old. The key to Mary's bone strength started with testosterone and estrogen replacement after her hysterectomy at age 46. She stays active with swimming and has brought back 10 Senior Olympic Gold Metals in her 80's.

Osteoporosis
The Merck Manual Home Edition
states:
"Osteoporosis is a progressive metabolic bone disease that decreases bone density (bone mass per unit volume), with deterioration of bone structure.
*Skeletal weakness leads to fractures with minor or inapparent trauma, particularly in the thoracic and lumbar spine, wrist, and hip (called fragility fractures).
*Diagnosis is by dual-energy x-ray absorptiometry (DXA scan) or by confirmation of a fragility fracture.
*Prevention and treatment involve risk factor modification, Ca and vitamin D supplements, exercises to maximize bone and muscle strength and minimize the risk of falls, and drug therapy to preserve bone mass or stimulate new bone formation.

Pathophysiology
Bone is continually being formed and resorbed. Normally, bone formation and resorption are closely balanced. Osteoblasts (cells that make the organic matrix of bone and then mineralize bone) and osteoclasts (cells that resorb bone) are regulated by parathyroid hormone (PTH), calcitonin, estrogen, vitamin D, various cytokines, and other local factors such as prostaglandins.

Peak bone mass in men and women occurs by the mid 20s. Blacks reach higher bone mass than whites and Asians, whereas Hispanics have intermediate values. Men have higher bone mass than women. After achieving peak, bone mass plateaus for about 10 yr, during which time bone formation approximately equals bone resorption. After this, bone loss occurs at a rate of about 0.3 to 0.5%/yr. Beginning with menopause, bone loss accelerates in women to about 3 to 5%/yr for about 5 to 7 yr and then the rate of loss decelerates.

Osteoporotic bone loss affects cortical and trabecular (cancellous) bone. Cortical thickness and the number and size of trabeculae decrease, resulting in increased porosity. Trabeculae may be disrupted or entirely absent. Trabecular bone loss occurs more rapidly than cortical bone loss because trabecular bone is more porous and bone turnover is higher. However, loss of both types contributes to skeletal fragility.

Fragility fractures: A fragility fracture occurs after less trauma than might be expected to fracture a normal bone. Falls from a standing height or less, including falls out of bed, are typically considered fragility fractures. The most common sites for fragility fractures are the distal radius, spine (vertebral compression fractures—the most common osteoporosis-related fracture), femoral neck, and greater trochanter. Other sites include the proximal humerus, pelvis, and metatarsals. However, metatarsal fragility fractures, unlike the others, do not necessarily constitute a need for pharmacologic therapy because current therapies have not been shown to reduce risk of metatarsal fractures.

Classification:
Osteoporosis can develop as a primary disorder or secondarily due to some other factor. The sites of fracture are similar in primary and secondary osteoporosis.

Primary osteoporosis: More than 95% of osteoporosis in women and probably about 80% in men is primary. Most cases occur in postmenopausal women and older men. Gonadal insufficiency is an important factor in both men and women. Other contributing factors may include decreased Ca intake, low vitamin D levels, and hyperparathyroidism. Some patients have an inadequate intake of Ca during the bone growth years of adolescence and thus never achieve peak bone mass.

The major mechanism of bone loss is increased bone resorption, resulting in decreased bone mass and microarchitectural deterioration, but sometimes bone formation is impaired. The mechanisms of bone loss may involve the following:
*Local changes in the production of bone-resorbing cytokines, such as increases in cytokines that stimulate bone resorption
*Impaired formation response during bone remodeling (probably caused by age-related decline in the number and activity of osteoblasts)
*Other factors such as a decline in local and systemic growth factors Fragility fractures rarely occur in children, adolescents, premenopausal women, or men < 50 yr with normal gonadal function and no detectable secondary cause, even in those with low bone mass (low Z-scores on dual-energy x-ray absorptiometry [DXA]—Bone density measurement). Such uncommon cases are considered idiopathic osteoporosis.

Secondary osteoporosis: Secondary osteoporosis accounts for < 5% of osteoporosis in women but probably more in men. The causes may also further accelerate bone loss and increase fracture risk in patients with primary osteoporosis.

Patients with chronic kidney disease may have several reasons for low bone mass, including hyperparathyroidism, renal osteodystrophy, and adynamic bone.

Causes of Secondary Osteoporosis:
*Cancer (eg, multiple myeloma)
*COPD (due to the disorder itself, as well as tobacco use and/or treatment with glucocorticoids)
*Chronic kidney disease
*Drugs (eg, glucocorticoids, anticonvulsants, medroxyprogesterone, aromatase inhibitors, rosiglitazone, pioglitazone, thyroid replacement therapy, heparin, ethanol, tobacco)
*Endocrine disease (eg, glucocorticoid excess, hyperparathyroidism, hyperthyroidism, hypogonadism, hyperprolactinemia, diabetes mellitus)
*Hypercalciuria
*Hypervitaminosis A
*Hypophosphatasia
*Immobilization
*Liver disease
*Malabsorption syndromes
*Prolonged weightlessness (as occurs in space flight)
*Rheumatoid arthritis

Risk Factors:

*Because stress, including weight bearing, is necessary for bone growth, immobilization or extended sedentary periods result in bone loss. A low body mass index predisposes to decreased bone mass. Certain ethnicities, including whites and Asians, have a higher risk of osteoporosis.
*Insufficient dietary intake of Ca, P, Mg, and vitamin D predisposes to bone loss, as does endogenous acidosis. Tobacco and alcohol use also adversely affect bone mass. A family history of osteoporosis, particularly a parental history of hip fracture, also increases risk. Patients who have had one fragility fracture are at increased risk of having other clinical (symptomatic) fractures and clinically asymptomatic vertebral compression fractures.

Symptoms and Signs:
Patients with osteoporosis are asymptomatic unless a fracture has occurred. Nonvertebral fractures are typically symptomatic, but about two thirds of vertebral compression fractures are asymptomatic (although patients may have underlying chronic back pain due to other causes such as osteoarthritis). A vertebral compression fracture that is symptomatic begins with acute onset of pain that usually does not radiate, is aggravated by weight bearing, may be accompanied by point spinal tenderness, and typically begins to subside in 1 wk. However, residual pain may last for months or be constant.

Multiple thoracic compression fractures eventually cause dorsal kyphosis, with exaggerated cervical lordosis (dowager's hump). Abnormal stress on the spinal muscles and ligaments may cause chronic, dull, aching pain, particularly in the lower back. Patients may have shortness of breath due to the reduced intrathoracic volume and/or abdominal discomfort due to the compression of the abdominal cavity as the rib cage approaches the pelvis.

Diagnosis:
*Dual-energy x-ray absorptiometry (DXA)
Bone density should be measured using DXA to screen people at risk and to follow patients with documented low bone density, including those undergoing treatment.
*Typically, DXA is done in all women ≥ 65 yr, women between menopause and 65 who have risk factors, including a family history of osteoporosis, a low body mass index (eg, previously defined as body weight < 127 lb), and use of tobacco and/or drugs with a high risk of bone loss (eg, glucocorticoids).
*DXA is also recommended for both men and women of any age who have had fragility fractures, older adults with unexplained sudden onset of back pain, patients with decreased bone density or asymptomatic vertebral compression fractures incidentally noted on imaging studies, and patients at risk of secondary osteoporosis.
*Although low bone density (and the associated increased risk of fracture) can be suggested by plain x-rays, it cannot be confirmed, and the diagnosis should be established by a bone density measurement.

It is not clear how often DXA should be repeated. For example, it can be done frequently (eg, every 2 yr) in women being treated for osteoporosis or who are at high risk, and can be done less frequently, sometimes much less frequently, in women who are at low risk (eg, T-scores < 2.00 and no risk factors).

*Plain x-rays: Bones show decreased radiodensity and loss of trabecular structure, but not until about 30% of bone has been lost. Loss of vertebral body height and increased biconcavity characterize vertebral compression fractures. Thoracic vertebral fractures may cause anterior wedging. In long bones, although the cortices may be thin, the periosteal surface remains smooth. Vertebral fractures at T4 or above raise concern of cancer rather than osteoporosis.

Glucocorticoid-induced osteoporosis is likely to cause rib fractures as well as fractures at other sites where osteoporotic fractures are common and exuberant callus formation at sites of healing fractures. Osteomalacia may cause abnormalities on imaging tests similar to those of osteoporosis. Hyperparathyroidism can be differentiated when it causes subperiosteal resorption or cystic bone lesions (rarely).

Osteopenia: Differentiating Osteoporosis and Osteomalacia
*Osteopenia is decreased bone mass. Two metabolic bone diseases decrease bone mass: osteoporosis and osteomalacia.
*In osteoporosis, bone mass decreases, but the ratio of bone mineral to bone matrix is normal.
*In osteomalacia, the ratio of bone mineral to bone matrix is low.
*Osteoporosis results from a combination of low peak bone mass, increased bone resorption, and impaired bone formation. Osteomalacia is due to impaired mineralization, usually because of severe vitamin D deficiency or abnormal vitamin D metabolism (see Vitamin D).
*Osteoporosis is much more common than osteomalacia in the US.
*The two disorders may coexist, and their clinical expression is similar; moreover, mild to moderate vitamin D deficiency can occur in osteoporosis.
*Osteomalacia should be suspected if the vitamin D level is consistently very low. To definitively differentiate between the two disorders, clinicians can do a tetracycline-labeled bone biopsy.
*Bone density measurement: DXA is used to measure bone mineral density (g/cm2); it is suggestive of osteopenia or osteoporosis (in the absence of osteomalacia), predicts the risk of fracture, and can be used to follow treatment response. Bone density of the lumbar spine, hip, distal radius, or the entire body can be measured. (Quantitative CT scanning can produce similar measurements of the spine or hip but is currently not widely available.) Bone density is ideally measured at three sites, including the lumbar spine and both hips. If one of these sites is not available for scanning (eg, because of hardware from prior total hip arthroplasty), the distal radius can be scanned. The distal radius should also be scanned in a patient with hyperparathyroidism because this is the most common site of bone loss in hyperparathyroidism.
*DXA results are reported as T-scores and Z-scores. The T-score corresponds to the number of standard deviations that the patient's bone density differs from the peak bone mass of a healthy, young person of the same sex and ethnicity. The WHO establishes cutoff values for T-scores that define osteopenia and osteoporosis. A T-score < -1.0 and > -2.5 defines osteopenia. A T-score ≤ -2.5 suggests osteoporosis.
*The Z-score corresponds to the number of standard deviations that the patient's bone mineral density differs from that of a person of the same age and sex and should be used for children, premenopausal women, or men < 50 yr. If the Z-score is ≤ -2.0, bone density is low for the patient's age and secondary causes of bone loss should be considered.

Current central DXA systems can also assess vertebral deformities in the lower thoracic and lumbar spine, a procedure termed vertebral fracture analysis (VFA). Vertebral deformities, even those clinically silent, are diagnostic of osteoporosis and are predictive of an increased risk of future fractures. VFA is more likely to be useful in patients with height loss ≥ 3 cm.

The need for drug therapy is based on the probability of fracture, which depends on DXA results as well as other factors. The fracture risk assessment (FRAX) score (WHO Fracture Risk Assessment Tool) predicts the 10-yr probability of a major osteoporotic (hip, spine, forearm, or humerus) or hip fracture. The score accounts for significant risk factors for bone loss and fracture. If the FRAX score is above certain thresholds (in the US, a ≥ 20% probability of major osteoporotic fracture or 3% probability of hip fracture), drug therapy should be recommended.

Monitoring for ongoing bone loss or the response to treatment with serial DXA scans should be done using the same DXA machine, and the comparison should use actual bone mineral density (g/cm2) rather than T-score. In patients being treated for osteoporosis, DXA should be repeated, usually about every 2 yr, but sometimes more frequently in patients taking glucocorticoids. A stable or improved bone mineral density indicates a lower fracture risk. Patients with as significantly decreased bone mineral density should be evaluated for drug adherence and secondary causes of bone loss.

Other testing:
An evaluation for secondary causes of bone loss should be considered in a patient with a Z-score ≤ -2.0 or if a cause of secondary bone loss is clinically suspected. Laboratory testing should usually include the following:
*Serum Ca, Mg, and P
*25-Hydroxy vitamin D level
*Liver function tests, including an alkaline phosphatase (hypophosphatasia)
*Intact PTH level (hyperparathyroidism)
*Serum testosterone in men (hypogonadism)
*24-h urine for Ca and creatinine (hypercalciuria)
*Other tests such as thyroid-stimulating hormone or free thyroxine to check for hyperthyroidism, measurements of urinary free cortisol, and blood counts and other tests to rule out cancer, especially myeloma (eg, serum and urine protein electrophoresis), should be considered depending on the clinical presentation.

Patients with chronic kidney disease can have low bone mass due to hyperparathyroidism, renal osteodystrophy, and adynamic bone, so they may need other tests.

Suggested Links:
*N.H.S. Choices (with Video)
*Medscape
*Osteoporosis in Review (professional)


Medications Used in Treatment:
1. Estrogens: Estrace®/estradiol; see list
2. Bisphosphonates: Actonel®/risedronate, Atelvia®/risedronate, Fosamax® Plus D/alendronate-cholcealciferol, Boniva®/ibandronate, Reclast®/zoledronic acid
3. Estrogen Angonist-Agonist: Evista®/raloxifene, Duavee®, Estra-Test® Covaryx®/estradiol/methyltestosterone
4. Anabolics: testosterone, compounded testosterone cream, Testopel®/testosterone implant, nandrolone, oxandrolone, stanozolol
5. Calcitonins: Miacalcin®/calcitonin salmon, Fortical®/calcitonin
6. Parathyroid hormone: Forteo®/ teriparatide
7. RANKL Inhibitors: Prolia®/denosumab
8. Interferon Gammas: Actimmune®/interferon Gamma-1b

*[Editor] Not only testosterone, but other anabolic steroids have a beneficial effect on osteoporosis in both sexes starting in middle age. The Japanese report that use of "Androgen inhibits osteoclastic bone resorption with increase of bone formation through androgen receptors in bone tissue...Some [anabolic steroids] have been approved as as drug for anti-osteoporosis. Anabolic steroids have also decreased fat mass with increase of lean body mass and muscle mass, and lessened bone pain in osteoporosis patients having bone fracture, which seem to be favorable effects for especially elder osteoporosis patients". Furthermore, nandrolone decanoate increases calcium balance and muscle mass, diminishes vertebral pain and increases the mobility of the spine.

*[Editor] Note that bisphosphonates offer no benefit to the aging male.

[Editor]: Osteoporosis Therapy in Postmenopausal Women with High Risk of Fracture in JAMA 2016, August 16 Vol. 316(7) stated "is a limit to how much bone strength can improve by reducing resorption in the absence of stimulating formation and rebuilding bone micro-architecture. Additional anabolic osteoporosis therapies are needed particularly on that have improved safety, efficacy, ease of administration and cost compared with teriparatide."

[Editor]: Troubling is a new study of a large database that links use of bisphonates with Age-related Macular Degeneration(AMD).

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