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Evaluation and treatment of premenopausal osteoporosis

BMD alone should not be used to define osteoporosis in a premenopausal woman but,
like fragility fractures, is an indication for further evaluation.

Bone density screening is not routinely recommended for premenopausal women .


BMD screening for premenopausal women if History of a fragility fracture Known
secondary causes of osteoporosis

The etiology of low bone mass in premenopausal women may be related to failure to
attain expected peak bone mass, previous bone loss, or ongoing bone loss. It is possible
that the patient never achieved optimal peak bone mass or that insults to the skeleton
occurred in the past and are no longer active; this can best be confirmed by serial bone
density or biochemical markers of bone turnover.

Premenopausal women who come to medical attention in the setting of a fragility


fracture or after learning of low bone mineral density (BMD) (Z-score -2.0) should
have an evaluation to identify potential secondary causes. All should have Complete
blood count Calcium, phosphate, creatinine Alkaline phosphatase, aminotransferases
25-hydroxyvitamin D Thyroid-stimulating hormone (TSH) 24-hour urine for
calcium and creatinine .Women with anemia, low urinary calcium excretion, and/or
low vitamin D levels should be tested for celiac disease. Serum parathyroid hormone
(PTH) and 1,25-dihydroxyvitamin D should be measured in patients with
hypercalcemia, hypercalciuria, or a history of renal stones. Urinary cortisol excretion
should be measured if Cushing's syndrome is suspected and also in patients with
unexplained osteoporotic fracture to assess for subcinical hypercortisol production

Some women may have genetically determined low peak bone mass. Other women may
have accrued less bone than expected due to insults to the skeleton (eg, medications,
poor nutrition, estrogen deficiency) that occurred during adolescence and are no longer
present at the time of evaluation. In either case, these women should have stable BMD,
even though BMD is low. This is in contrast to women with continued declines in BMD
who may have an ongoing secondary cause. Serial BMD measurements, if available, are
helpful in making this distinction. If there is only a single measurement of BMD,
obtaining serum or urinary markers of bone turnover may provide useful information.
Specimens must often be collected fasting in the morning If markers of resorption are
elevated above the premenopausal range, ongoing bone resorption is more likely.
Adolescence and young adulthood are characterized by active bone modeling and
physiologic increases in markers of bone turnover. Additionally, elevated bone turnover
markers are expected after a recent fracture. Premenopausal women with bone fragility
and no identifiable etiology after extensive evaluation for secondary causes are said to
have idiopathic osteoporosis. In patients with a history of fragility fractures without a
known cause, iliac crest bone biopsy may be indicated to identify other sources of bone
fragility

TREATMENT Calcium 100mg , vitamin D 600 U day , and weightbearing exercise


.Medications are usually reserved for those with fracture(s), active bone loss, and/or
known ongoing secondary causes of osteoporosis and bone loss.

Fractures or accelerated bone loss if hypogonadism may benefit from estrogen


replacement. However, oral reproductive hormone replacement has been shown to be
ineffective in most studies examining bone mass in anorexia nervosa . In women with
normal gonadal function or in those who cannot take estrogen, bisphosphonates and
teriparatide are generally the drugs of choice in the rare cases when pharmacologic
therapy is indicated (fragility fractures or accelerated bone loss [approximately 4
percent/year, depending on clinical setting]). Also ok if chronic glucocorticoids. For
women with osteogenesis imperfecta, bisphosphonates are the treatment of choice.

Without fractures or accelerated bone loss In premenopausal women with low


bone mineral density (BMD) alone (without fractures, known secondary causes for low
BMD, or evidence of accelerated bone loss), pharmacotherapy is almost never
indicated. If markers of bone turnover are in the lower end of normal range for
premenopausal women and serial BMD measurements are not available, it may be
reasonable to treat with calcium and vitamin D and repeat a bone density study in one to
two years.

Subcutaneous PTH (teriparatide) has been used successfully to prevent bone loss in
premenopausal women on gonadotropin-releasing hormone (GnRH) agonists for the
treatment of endometriosis , in premenopausal women taking glucocorticoids [47,48], in
premenopausal women with idiopathic osteoporosis [49], and in those with AN [50].
Additionally, a case series documented benefit in pregnancy-associated osteoporosis
[51]. Teriparatide is currently approved for the treatment of glucocorticoid-induced
osteoporosis. Teriparatide has been associated with osteosarcoma in rodent studies. Use
of this medication should be avoided in those at increased risk of osteosarcoma
(including those with Paget disease, prior radiation, growing bones (open epiphyses), or
unexplained elevation in alkaline phosphatase). Thus, this medication should be used
with great caution in young women, and use should be avoided in those with delayed
growth or open epiphyses.

SERMs such as raloxifene and tamoxifen should not be used to treat osteoporosis in
menstruating women, as they block estrogen action on bone, leading to further bone
loss.

Denosumab pregnancy category X. No studies in premenopausal women done

Glucocorticoids Glucocorticoids reduce the production of sex steroids. As a result, it


is logical to replace these hormones if the patient is deficient We typically reserve the
use of bisphosphonates for premenopausal women taking or initiating glucocorticoids
(7.5 mg/day prednisone equivalent), who have a fragility fracture or accelerated bone
loss (approximately 4 percent/year, depending on clinical setting), and who are not
candidates for or are intolerant of estrogen replacement therapy (eg, oral
contraceptives). Teriparatide is an alternative option for women with fully fused
epiphyses who have glucocorticoid-induced osteoporosis and fragility fractures,
particularly at the spine.

Chemotherapy For women with chemotherapy-induced menopause and low BMD


(T-score <-2.5) and/or fragility fracture, we suggest bisphosphonates.
Bisphosphonates successfully prevent bone loss in premenopausal women with newly
diagnosed breast cancer treated with chemotherapy and/or tamoxifen

Eliminating gluten from the diet of young women diagnosed with celiac disease leads
to marked improvement in BMD Parathyroidectomy in premenopausal women with
primary hyperparathyroidism results in improvement in BMD. Weight gain and
resumption of normal menstrual function appears necessary for skeletal recovery in
patients with Anorexia nervosa N (see "Anorexia nervosa: Endocrine complications and
their management"). However,

Secondary causes of osteoporosis in premenopausal women


Anorexia nervosa
Gastrointestinal malabsorption (eg, celiac disease, postoperative states)
Vitamin D and/or calcium deficiency
Hyperthyroidism
Hyperparathyroidism
Cushing's syndrome
Hypogonadism (hypogonadotropic or hypergonadotropic)
Hypercalciuria
Rheumatoid arthritis and other inflammatory conditions
Alcoholism
Renal disease
Liver disease
Osteogenesis imperfecta
Systemic mastocytosis
Marfan's syndrome and Ehlers-Danlos syndrome
Homocystinuria
Hereditary hemochromatosis
Thalassemia major
Gaucher disease
HIV infection and/or medications
Diabetes (types 1 and 2)
Medications
Glucocorticoids
Immunosuppressants (cyclosporine)
Antiseizure medications (particularly phenobarbital and phenytoin)
GnRH agonists (when used to suppress ovulation)
Heparin
Chemotherapy leading to amenorrhea
Thiazolidinediones
Depot medroxyprogesterone acetate
Possible contributors
Excess thyroid hormone
Depression and/or SSRI use
Proton pump inhibitors

Tx postmenopausal women and men 50 years of age


History of hip or vertebral fracture.
T-score -2.5 (DXA) at the femoral neck or spine, .
T-score between -1 and -2.5 at the femoral neck or spine, and a 10-year probability of
hip fracture 3 percent or a 10-year probability of any major osteoporosis-related
fracture 20 percent

linical risk factors for fracture


Advancing age
Previous fracture
Glucocorticoid therapy
Parental history of hip fracture
Low body weight
Current cigarette smoking
Excessive alcohol consumption
Rheumatoid arthritis
Secondary osteoporosis (eg, hypogonadism or premature menopause, malabsorption, chronic liver disease,
inflammatory bowel disease)

Secondary causes of osteoporosis in postmenopausal women


Marrow-related disorders
Drugs
Amyloidosis
Glucocorticoids
Hemochromatosis
Immunosuppressants (cyclosporine)
Hemophilia
Antiseizure medications (particularly
phenobarbital and phenytoin) Leukemia
GnRH agonists and antagonists Lymphoma
Heparin Mastocytosis
Cancer chemotherapy Multiple myeloma
Endocrine disorders Pernicious anemia
Acromegaly Sarcoidosis
Adrenal insufficiency Sickle cell anemia
Cushing's syndrome Thalassemia
Eating disorders Organ transplantation
Endometriosis Bone marrow
Hyperparathyroidism Heart
Hyperprolactinemia Kidney
Hyperthyroidism Liver
Hypogonadism (primary or secondary) Lung
Diabetes mellitus Miscellaneous causes
Gastrointestinal disease/nutritional disorders Ankylosing spondylitis
Alcohol-related liver disease Chronic obstructive pulmonary
disease
Celiac disease
Congenital porphyria
Chronic active hepatitis
Epidermolysis bullosa
Chronic cholestatic disease
Hemophilia
Gastrectomy
Idiopathic hypercalciuria
Inflammatory bowel disease
Idiopathic scoliosis
Jejunoileal bypass
Multiple sclerosis
Malabsorption syndromes
Rheumatoid arthritis
Pancreatic insufficiency
Genetic disorders
Parenteral nutrition
Hypophosphatasia
Primary biliary cholangitis
Osteogenesis imperfecta
Severe liver disease
Homocystinuria due to cystathionine
Vitamin D and/or calcium deficiency
deficiency

Initial laboratory tests


Complete chemistry profile (including alkaline phosphatase)
Complete blood count
Calcium, phosphorus
25-hydroxyvitamin D
Additional laboratory tests if indicated
24-hour urine for calcium and creatinine
24-hour urine for free cortisol
Estradiol
FSH, LH
Prolactin
Magnesium
1,25-dihydroxyvitamin D
Intact PTH
TSH
Celiac screen
Serum protein electrophoresis/urine protein electrophoresis
Erythrocyte sedimentation rate
Rheumatoid factor
Ferritin and carotene levels
Iron and total iron binding capacity
Serum tryptase and histamine levels
Homocysteine
Skin biopsy for connective tissue disorders
COL1A genetic testing for osteogenesis imperfecta
Serum and urine markers of bone turnover

DIFFERENTIAL DIAGNOSIS . The main casue for steoporosis in post menop woemn
is loss of estrogen and with it increased bone resorbtion . Other causes of bone
fractures and reduced bone mineral density (BMD) include osteomalacia, malignancy
(eg, multiple myeloma), Paget disease, and hyperparathyroidism. Physical abuse should
always be considered a possibility Low BMD may also be seen in conjunction with
renal osteodystrophy in patients with decreased kidney function

Tx oral bisphosphonates as first-line therapy.For patients with severe osteoporosis (T-


score of -3.5 or below even in the absence of fractures, or T-score of -2.5 or below plus
a fragility fracture), initial treatment with teriparatide is an alternative. Because
treatment with teriparatide is limited to 24 months, patients with severe osteoporosis
who are treated with teriparatide first are typically treated with an antiresorptive agent
(eg, bisphosphonates) after discontinuing teriparatide.

For patients with esophageal disorders, gastrointestinal intolerance, history of Roux-en-


Y gastric bypass, or an inability to follow the dosing requirements of oral
bisphosphonates, including an inability to sit upright for 30 to 60 minutes and/or to
swallow a pill, we suggest iv zoledronic acid, Oral and IV bisphosphonates should not
be used routinely in patients with CKD and an eGFR <30 to 35 mL/min.
For patients who cannot receive or are intolerant of oral and IV bisphosphonates,
options include teriparatide, denosumab, or SERMs. For postmenopausal women with
severe osteoporosis (T-score of -3.5 or below even in the absence of fractures, or T-
score of -2.5 or below plus a fragility fracture), we prefer teriparatide for up to 2
yearfollowed by desonumap .For patients who do not meet criteria for severe
osteoporosis but have had fragility fractures, denosumab rather than teriparatide is a
reasonable option, particularly in patients with impaired renal function.

Fracture while taking bisphosphonates Switching to teriparatide is a good option


for patients with severe osteoporosis (T-score <-2.5 and at least one fragility fracture)
who continue to fracture after one year of bisphosphonates

Clinical manifestations, diagnosis, and evaluation of osteoporosis in men

Osteoporosis has no clinical manifestations until there is a fracture.Men may also have
symptoms of disorders that are known to cause osteoporosis, such as hypogonadism,
malabsorption, and hyperparathyroidism

There is an increased risk of fracture, particularly at the spine, hip, wrist, humerus, rib,
and pelvis. Age 50 years use the same classification of BMD to define osteoporosis
in men (age 50 and older) as in women ,a value for BMD 2.5 or more standard
deviations below the young healthy male reference mean (rather than female reference
mean). Age <50 years In men below age 50 years with low BMD (Z-score -2.0), we
diagnose osteoporosis if there is a history of a fragility fracture and, possibly, if other
risk factors for osteoporosis (such as glucocorticoid therapy, hypogonadism, or
hyperparathyroidism) are present.

CANDIDATES FOR BONE DENSITY TESTING Clinical manifestations of low


bone mass, such as radiographic osteopenia, history of low trauma fractures, or loss of
more than 1.5 inches in height.Risk factors for fracture, such as long-term
glucocorticoid therapy, androgen deprivation therapy for prostate cancer,
hypogonadism, primary hyperparathyroidism, and intestinal . Some experts recommend
BMD testing for all men older than 70 years and in men 50 to 70 years when risk
factors are present. In men who are candidates for BMD testing, we suggest dual-energy
x-ray absorptiometry (DXA) measurements of the spine and hip because fractures at
these sites have the greatest impact on patients' health. Measurement of hip BMD also
has the highest predictive value for hip fracture. In addition, if pharmacologic therapy is
planned, measurement of spine BMD is useful as it shows less variability and can detect
responses to therapy earlier than hip BMD.

In men with clinical manifestations of osteoporosis (low trauma fracture) or with low
bone mass by dual-energy x-ray absorptiometry (DXA) (T-score less than -2.0), an
initial evaluation for secondary causes of osteoporosis (such as renal or liver disease,
hyperparathyroidism, Cushing's syndrome, celiac disease and other forms of
malabsorption, or idiopathic hypercalciuria) should be performed.

Routine biochemical tests to uncover renal or hepatic disease, a complete blood count,
serum testosterone, calcium, alkaline phosphatase, 25-hydroxyvitamin D (calcidiol),
and 24-hour urine calcium and creatinine (table 3).
Other Parathyroid hormone Estradiol In adult men with acquired hypogonadism,
estrogen deficiency may contribute more to bone loss than does androgen deficiency,
particularly if levels are below 10 to 15 pg/mL Tissue transglutaminase antibodies to
screen for celiac disease We typically measure this in men who have a low 25-
hydroxyvitamin D level and/or low urinary calcium. Serum and urine protein
electrophoresis Markers of bone formation and resorption as serum bone-specific
alkaline phosphatase concentrations and urinary excretion of deoxypyridinoline 24-
hour urinary free cortisol Serum tryptase to screen for systemic mastocytosis if
fractures, unexplained osteoporosis, or bone pain. In rare cases, iliac crest bone biopsy

Causes of osteoporosis in men


Connective tissue diseases
Osteogenesis imperfecta
Endocrine diseases
Ehlers-Danlos syndrome
Hypogonadism
Marfan's syndrome
Primary
Homocystinuria
Secondary
Drugs
Delayed puberty
Alcohol
Estrogen deficiency
Heparin
Hypercortisolism
Glucocorticoids
Hyperthyroidism
Thyroxine suppressive therapy
Hyperparathyroidism
Anticonvulsant drugs
Vitamin D deficiency
Gonadotropin-releasing hormone analogs
Growth hormone deficiency
Cyclosporine
Diabetes mellitus (type 1 and 2)
Chemotherapy
Gastrointestinal diseases
HIV medications (eg, tenofovir)
Malabsorption syndromes (eg, celiac disease, postoperative states)
Miscellaneous causes
Inflammatory bowel disease
Eating disorders (eg, anorexia nervosa)
Cirrhosis
Hypercalciuria
Hematologic disorders
Immobilization
Multiple myeloma
Rheumatoid arthritis
Chronic hemolytic anemia
Renal disease
Systemic mastocytosis
Hepatic disease
Tobacco

Laboratory evaluation for men osteoporosis


Initial laboratory tests
Complete chemistry profile (including alkaline phosphatase)
Complete blood count
Calcium, phosphorus
25-hydroxyvitamin D
Testosterone
Urinary calcium excretion
Additional laboratory tests if indicated
24-hour urine for free cortisol
FSH, LH
Estradiol
Prolactin
Magnesium
1,25-dihydroxyvitamin D
Intact PTH
TSH
Celiac screen
Serum protein electrophoresis/urine protein electrophoresis
Erythrocyte sedimentation rate
Rheumatoid factor
Ferritin
Iron and total iron binding capacity
Serum tryptase and histamine levels
Homocysteine
Skin biopsy for connective tissue disorders
COL1A genetic testing for osteogenesis imperfecta
Serum and urine markers of bone turnover

A value for BMD within 1 SD of the young adult female


Normal
reference mean (T-score greater than or equal to -1 SD).
A value for BMD more than 1 but less than 2.5 SD below the
Low bone mass
young adult female reference mean (T-score less than -1 and
(osteopenia)
greater than -2.5 SD).
A value for BMD 2.5 or more SD below the young adult female
Osteoporosis
reference mean (T-score less than or equal to -2.5 SD).
Severe (established) A value for BMD more than 2.5 SD below the young adult female
osteoporosis reference mean in the presence of one or more fragility fractures.

Treatment calcium (1000 mg/day in younger men, 1000 to 1200 mg daily in older men,
total diet plus supplement) and vitamin D (600 to 800 international units/day)

Testosterone therapy testosterone replacement therapy for hypogonadal men (as


evidenced by clinical symptoms and signs consistent with androgen deficiency and a
distinctly subnormal serum testosterone concentration) or men who have an
unequivocal cause for hypogonadism (eg, pituitary tumor, Klinefelter syndrome,
gonadotropin-releasing hormone [GnRH] deficiency, etc) and who do not have
contraindications to testosterone therapy.

For the treatment of men with osteoporosis (T-score below -2.5 or fragility fracture)
who do not have symptomatic hypogonadism or in hypogonadal men in whom
testosterone therapy is contraindicated, we recommend pharmacologic therapy. For the
treatment of high-risk men with T-scores between -1.0 and -2.5, also suggest
pharmacologic therapy. Especially if a 10-year probability of hip fracture or combined
major osteoporotic fracture of 3.0 or 20 percent, respectively.

Guidelines suggest adding a pharmacologic agent with proven antifracture efficacy (eg,
a bisphosphonate or teriparatide) in hypogonadal men whose risk of fracture is felt to be
high High-risk groups might include men on high-dose glucocorticoids; men with
frequent falls; men who have had a recent fragility fracture, particularly if they have a
BMD T-score below -2.5 at any skeletal site; or men with T-scores below -3.5 or even
below -3 if they have other risk factors for fracture. Adding an established osteoporosis
therapy to testosterone should also be considered in hypogonadal men whose BMD T-
score is <-2.5 even after receiving adequate testosterone replacement therapy for two
years.

Guidelines recommend treatment of men 50 years with a history of hip or vertebral


fracture or with osteoporosis based upon BMD measurement (T-score -2.5). If men
with osteopenia on BMD (T-score between -1.0 and -2.5,treat if 10-year probability of
hip fracture reaches 3 percent or the 10-year probability of osteoporotic fractures
combined is 20 percent

Choice of therapy Men seem to respond to available therapies in the same way that
women respond so that, for the most part (notable exceptions being male
hypogonadism), the approach to treating men and women with osteoporosis is quite
similar. Bisphosphonates are considered the treatment of choice such as weekly
alendronate or risedronate as initial therapy for most men . Men who have esophageal
disorders (achalasia, scleroderma involving the esophagus, esophageal strictures,
varices), gastrointestinal intolerance to oral bisphosphonates, or an inability to follow
the dosing requirements of oral bisphosphonates can be treated instead with
intravenous (IV) bisphosphonate therapy. Oral bisphosphonates should also be avoided
after certain types of bariatric surgery in which surgical anastomoses are present in the
gastrointestinal tract (eg, Roux-en-Y gastric bypass); IV bisphosphonates are acceptable
as long as vitamin D has been assessed and is in the normal range. Zoledronic acid (ZA)
is the only IV bisphosphonate that has demonstrated efficacy for fracture

Denosumab is an alternative option for men who cannot tolerate oral or IV


bisphosphonates or who have difficulty with the dosing requirements and have impaired
renal function. However, denosumab has not yet been shown to prevent fracture in men,
except for men with prostate cancer receiving androgen deprivation therapy.
Teriparatide, an anabolic agent, is also available and is generally reserved for men with
severe osteoporosis (low BMD [T-score <-2.5] and at least one fragility fracture), or
men who have failed previous therapy (eg, continue to fracture after one year of
bisphosphonate therapy).

Patients with kidney disease and estimated glomerular filtration rate (eGFR) >30 to 35
mL/min are managed similarly, as long as there are no accompanying biochemical
abnormalities (eg, hyperparathyroidism, hyperphosphatemia) that indicate the
coexistence of renal osteodystrophy. Bisphosphonates are generally not recommended
for those with eGFR below 30 to 35 mL/min.

Stopping therapy after three to five years (a "drug holiday") may be reasonable for
some men,. For men taking alendronate for five years or who received ZA once yearly
for three years, who have a stable BMD, no previous fragility fractures, and who are at
low risk for fracture in the near future, we suggest discontinuing the drug. BMD should
be monitored every two years after suspending therapy, and therapy should generally be
resumed if BMD declines significantly or if the patient develops a new fragility fracture.

adding a bisphosphonate to teriparatide (either started concurrently or prior to PTH)


offers no additional benefit . However, the immediate use of bisphosphonates after
teriparatide is withdrawn appears to help optimize gains in BMD at the lumbar spine

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