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osteoporosis

Definitions: 1) low bone mass with a normal ratio of mineral to osteoid 2) generalized skeletal fragility in which bone strength is sufficiently weak that fractures occur with minimal trauma 3) low bone mass & microarchitectural deterioration of bone tissue leading to enhanced bone fragility & consequent increase in fracture risk 4) DEXA T-score of <= -2.5 defines osteoporosis [7] 5) minimal trauma fracture of the spine, proximal humerus, hip, or forearm [88] Etiology: 1) primary (most common) a) postmenopausal women (1), estrogen deficiency b) men testosterone deficiency c) senile (2) d) idiopathic in younger men & women 2) secondary a) endocrine disorders - Cushing's syndrome - hyperthyroidism - hyperparathyroidism - diabetes mellitus type 1 - acromegaly - hypogonadism in men b) hematopoietic disorders - multiple myeloma - sickle cell disease - thalassemia minor - leukemia - lymphoma - polycythemia vera c) connective tissue disorders - osteogenesis imperfecta - rheumatoid arthritis - homocystinuria d) kidney disease - chronic renal failure - renal tubular acidosis - hypercalciuria e) immobilization f) disseminated malignancy g) nutritional - malabsorption - celiac disease, Crohn's disease, intestinal resection - total parenteral nutrition - vitamin D deficiency h) gastrointestinal disorders - Crohn's disease - intestinal resection - celiac sprue [2] - gastrectomy - primary biliary cirrhosis i) genetic disorders - Turner syndrome - Kleinfelter syndrome - hypercalciuria j) pharmacologic causes: - glucocorticoids - androgen deprivation therapy - aromatase inhibitors [88] - chronic heparin administration - thyroxine with suppressed TSH - cancer chemotherapy [88] - anticonvulsants: phenobarbital, phenytoin - proton pump inhibitors [88] - antiretroviral agents [88] - SSRIs [88] - methotrexate [88] - cyclosporine - high intake of vitamin A [4] - interferes with action of vitamin D - canagliflozin [96] - thiazolidinediones - pioglitazone - see pharmaceutical agents that cause bone loss k) solid organ transplantation 3) major risk factors a) age (post-menopausal women, men > 70 years) [88] b) female sex c) early menopause d) androgen-deprivation therapy in men [7,39] e) Caucasian or Asian f) glucocorticoids g) low lean body mass (BMI < 20 kg/m2) [7] 4) minor risk factors a) positive family history of osteoporosis b) low calcium intake c) lack of exercise d) smoking [7] e) alcoholism (> 2 drinks/day) f) rheumatoid arthritis [88] g) major depression & borderline personality disorder [29] h) depression [37] i) psoriasis in men [42] j) spinal cord injury [7] k) drinking carbonated beverages (colas) containing phosphoric acid NOT risk factor [20] Epidemiology: 1) largely, but not exclusively a disease of women a) 20% of all osteoporotic fractures occur in men b) 1/3 of hip fractures in patients > 75 years of age occur in men 2) osteoporosis manifests itself clinically ~10 years after menopause 3) peak incidence in the 60s & early 70s 4) senile osteoporosis presents after age 70 in either sex a) 39% of women over 70 have osteoporosis at any site b) 25% of women over 70 have osteoporosis at the hip a) 70% of women over 80 have osteoporosis at any site b) 48% of women over 80 have osteoporosis at the hip Pathology: 1) postmenopausal osteoporosis a) enhanced bone resorption during 1st 7 years after menopause b) predominantly trabecular bone is lost c) loss of up to 2-4% of bone mineral density/year d) up to 1/4-1/3 of bone mineral density may be lost in 7 years e) after 7 years rate of bone loss slows to same rate as that of men 2) senile osteoporosis a) both cortical & trabecular bone is lost b) defective bone formation may be involved Genetics: - homozygosity for XbaI polymorphism of estrogen receptor- alpha gene may reduce risk of vertebral (RR = 0.65) & hip fracture (RR = 0.81) without increasing bone mineral density [23] - defects in LRP5 are associated susceptibility to osteoporosis - polymorphisms in COL1A1 may be associated with susceptibility to osteoporosis - polymorphisms in CALCR may be correlated with low bone mineral density, osteoporosis History: - family history of osteoporosis - medication history - history of previous fracture - history of height loss * also see etiology Physical examination: - BMI - gait & balance assessment - palpation of spine for point tenderness - assessment of kyphosis Clinical manifestations: 1) postmenopausal osteoporosis a) vertebral crush fractures b) Colle's fractures of the distal forearm c) acute or chronic back pain d) kyphosis c) loss of height 2) senile osteoporosis a) increased risk of vertebral & hip fractures b) vertebral fractures may cause back pain & kyphosis c) hip fractures are more serious, causing considerable morbidity & mortality 3) minimal trauma fracture defines osteoporosis [2] Laboratory: 1) biochemical profile to evaluate renal & hepatic function, primary hyperparathyroidism* & nutritional status [14] a) complete blood count (CBC) b) basic metabolic panel c) liver function tests d) serum phosphorus [7] e) serum PTH* [7] 2) serum testosterone [7] - free testosterone (pooled) 3) serum 25-OH vitamin D3 a) Institute of Medicine recommends levels > 20 ng/mL b) other experts recommend levels > 30 ng/mL [7] 4) serum osteocalcin & serum alkaline phosphatase (bone) can be used to follow antiresorptive therapy 5) urinalysis - 24 hour urine a) 24 hour urine calcium or calcium/creatinine - < 100 mg/24 hours suggests calcium deficiency b) cross-linked N-telopeptides (OsteoMark) 6) serum TSH (check prior to initiating bisphosphonate) [2] 7) serum protein electrophoresis (SPE) 8) erythrocyte sedimentation rate [2] 9) tissue transglutaminase IgA in serum if celiac disease suspected 10) in the absence of bone fracture laboratory values are generally normal with primary osteoporosis [2] 11) see ARUP consult [48] * serum PTH not needed unless specifially indicated [14] Radiology: 1) Dual-energy radiography (DEXA) - measures bone mass of thelumbar spine & proximal femur with high precision - screening beginning at age 65 (USPSTF) & screen women < 65 if their 10-year fracture risk >= that of a woman > 65 without additional risk factors ~ 9% [8,80] - use WHO's FRAX tool to estimate fracture risk - obtain Dexa scan as baseline if patient meets criteria for osteoporosis regardless of whether or not it will affec management - men >= 70 years & younger if risk factors (smoking, low BMI, previous fracture, androgen-deprivation therapy)[47] - recommendations apply to all racial & ethnic groups - repeat measurement may be of little benefit in predicting risk of fracture [30,74] - repeat DEXA is useful in predicting fracture risk [76] - ref [2] recommends repeat DEXA in 2 years for women with osteopenia not meeting criteria for treatment - radiology review of unexpected findings prior to change in management [7] - T-score of <= -2.5 defines osteoporosis [7] - threshold for treatment may be Z-score of < -1.8 - Endocrine Society recommends monitoring bone-mineral density every 1-3 years for postmenopausal women receiving treatment for osteoporosis [86] - monitoring during therapy of no benefit [77,88]* - ref [76] recommends repeat DEXA 2-3 years after initiating therapy, then again at 5 years - ref [2] recommends repeat DEXA 12-24 months after initiating therapy (since [2] is MKSAP & [77] is ACP (more recent) probably deprecated) - ref [47] recommends repeat DEXA every 1-2 years for men receiving treatment for osteoporosis - include distal 3rd of radius in patients with hyperparathyroidism [95] 2) dual- or single-energy radiography using forearm, finger or heel is a less expensive, office-based test which shows promise [5] 3) ultrasound of calcaneus may offer alternative to DEXA [16] 4) screening with DEXA reduces risk of hip fracture for individuals > 85 years of age [26] 5) abdominal CT for other reasons may reveal vertebral osteoporosis [53] 6) radiography of lumbar spine & thoracic spine to assess for vertebral fracture - pathologic fracture makes diagnosis of osteoporosis [] * seems to be accepted guideline Complications: 1) fracture, especially a) hip fracture b) vertebral compression fracture* c) osteoporotic fractures are associated with increased mortality [41] d) for risk calculotor, see [63] 2) independent cardiac risk factor [20] 3) benign positional vertigo [7,61] * vertebral compression fracture makes diagnosis of osteoporosis regardless of bone mineral density T-score [2] Differential diagnosis: - osteomalacia: - hypophosphatemia, hypocalcemia, elevated serum alkaline phosphase - bone pain, aching pain with weight bearing, proximal muscle weakness - Paget's disease of bone - increased serum alkaline phosphatase - hyperparathyroidism (hypercalcemia, normal PTH upper 1/2 of reference interval) [2] Management: 1) parathyroidectomy for hyperparathyroidism & osteoporosis (see differential diagnosis) [2] 2) indications for initiation of therapy - bone mineral density T score < -2.5 at the femoral neck, total hip, or spine by DXA, after appropriate evaluation [38] men or women [47] - postmenopausal women at high fracture risk, particularly patients with recent fracture [86] - drug treatment not associated with diminished mortality [33] 3) FRAX tool & QFracture evaluate risk of fracture - FRAX treatment thresholds: - >= 20% 10 year risk of major osteoporotic fracture - bisphosphonate therapy recommended [95] - >= 3% 10 year risk of hip fracture [2] - bone mineral density (BMD) indicated if FRAX score >= 9.3% [2] 4) also see recommendations for treatment of osteopenia 5) calcium (CaCO3: calcium/magnesium citrate may be better) a) 1000 mg QD for premenopausal women & postmenopausal women under 65 on estrogen replacement therapy b) 1200 mg of calcium QD for older women - prevents bone loss - decreases fracture risk ~12% relative to lesser amounts [7], [65] fails to confirm c) men at risk: [47] - 1000-1200 mg of calcium/day preferably from dietary sources - vitamin supplements if serum 25-hydroxyvitamin D < 30 ng/mL d) calcium supplements do NOT increase bone density, but attenuate bone loss e) calcium supplements decrease risk of fracture [35] - treatment of 63 elderly for 3.5 years to prevent 1 fracture [35] f) caution: calcium supplementation may be associated with increased risk of myocardial infarction (see calcium supplement) g) 800 IU of vitamin D3 QD may be prudent [27] - vitamin D 50,000 IU weekly for 6-12 weeks for vitamin D deficiency - calcium 1200 mg/day for men & women > 50 years preferably from dietary sources & vitamin D 600 IU/day, 800 IU/day recommended for elderly > 71 years [7] - 1000 mg of Ca+2 + 400 IU of vitamin D3 does not prevent fractures (see Women's Health Initiative) - supplemental calcium needed to reduce risk of hip fracture with vitamin D supplementation [51] h) sunlight not recommended by American Academy of Dermatology i) patients receiving glucocorticoids for more than 1-2 weeks should receive calcium & vit D supplementation j) adequate calcium intake is achieved through diet for most populations [7] - dietary calcium* is preferred over calcium supplements for prevention of osteoporosis [7] (see dietary calcium) - high dietary calcium without benefit on fracture risk [45] - low dietary calcium associated with increased risk of fracture [45] - calcium supplements &/or dietary calcium may not reduce risk of fractures [65] - high dietary calcium + bisphosphonate +/- vitamin D is treatment of choice [7] 6) bisphosphonates a) first line therapy [2,92] - expected time-to-benefit is 1-2 years [7] - begin after correction of vitamin D deficiency with resultant secondary hyperparathyroidism [95] b) increase bone mineral density (vertebral & hip) - do not diminish mortality [87] c) alendronate, risedronate & zoledronate prevent hip fractures, vertebral fractures & other factures [66] - avoid if creatinine clearance < 35 mL/min - GRS11 describes case with CKD3B (unspecified eGFR) & recommends alendronate [7] d) ibandronate diminishes risk of vertebral fractures [66] - 150 mg/month or 3 mg IV every 3 months (treatment only) [88] e) alendronate - 10 mg PO QD or 70 mg weekly (treatment) - 35 mg weekly (prophylaxis) [88] - reassess risk after 5 years [67] (see bisphosphonate) - benefit/risk ratio remains favorable for > 10 years in postmenopausal women with osteoporosis [75] - osteoporosis refractory to oral bisphosphonate should be treated with IV zoledronate, denosumab or romosozumab [56,79,84,85] - fragility fracture (pathologic fracture) unless it occurs 6-12 months after initiation of therapy does not indicate refractory to therapy & warrant a change in therapy [7,85] r) residronate 5 mg PO QD or 35 mg weekly or 150 mg/month t) see Fosamax Actonel Comparison Trial h) zoledronate (Zometa) - 5 mg IV every 2 years (prophylaxis) - 5 mg IV yearly (treatment) - useful for women refractory to alendronate [84,85] - decreases vertebral fracture risk in men [50] - yearly zoledronate increases bone density & decreases bone turnover similarly to weekly alendronate [60] - reassess risk after 3 years [63,67] (see zoledronate, bisphosphonate) i) duration of therapy 5 years [77] - reassess need for bisphosphonate after 3-5 years [86] - reassess after 3 years IV, 5 years oral bisphosphonate [2] - patients at low-to-moderate risk may take a bisphosphonate holiday [86] 7) denosumab (Prolia) - 2nd line therapy (bisphosphate contraindicated or adverse effects) [92] - 60 mg SC every 6 months - effective in patients with renal failure (chronic renal failure stage G4, G5?) - useful for women refractory to alendronate [84,85] - men on androgen deprivation therapy for prostate cancer at high risk of fracture [49] - denosumab plus teriparatide better than either drug alone for increasing bone mineral density in postmenopausal women [54] - for the relatively few patients at very high fracture risk, combination treatment with teriparatide plus denosumab for 1-2 years followed by denosumab monotherapy [64] - for most patients with osteoporosis, combination therapy with teriparatide is not indicated [64] - treatment with denosumab followed by teriparatide is not recommended [64] - denosumab prevents hip fractures, vertebral fractures & other factures [66] - duration of therapy - bone resorption transiently increases dramatically upon cessation of therapy, increasing risk of vertebral fractures [2] - no established duration of therapy [2] - duration of therapy 5 years [77] - safe for 10 years of therapy [89] - continued increases in bone mineral density without plateau - reassess need for denosumab after 5-10 years [86] 8) patients receiving long-term glucocorticoids - fracture risk should be assessed within 6 months - bone mineral density - use of FRAX tool for adults > 40 years of age - reassess fracture risk every 12 months [78] - calcium supplement,vitamin D & a bisphosphonate [2,55,78] 9) raloxifene (Evista) a) increases vertebral bone mineral density b) diminished risk of vertebral fractures - does not diminish risk of hip fracture [66] c) for women who cannot tolerate bisphosphonate [2] d) clinicians should not prescribe raloxifene to treat women with osteoporosis [77] 10) calcitonin nasal spray a) bisphosphonates & raloxifene contraindicated b) relief of pain from osteoporotic fractures 11) parathyroid hormone a) PTH 1-34 (teriparatide {Forteo} 20-40 ug SQ QD [9] b) indications: severe osteoporosis with fractures [2] - preferred over raloxifene or calcitonin for women intolerant of bisphosphonates with prior vertebral fracture [7] c) in women with prior vertebral fractures reduces vertebral fractures by 65% - reduces non-vertebral fractures by 53% [7] d) combined Forteo + Fosamax less effective than Forteo alone [15] e) recombinant PTH 1-84 100 ug SQ QD may reduce risk of vertebral fractures, but adverse effects common [33] f) increases bone mineral density, reduces vertebral fractures but not other fractures, relative to alendronate [36] g) daily teriparatide 20 ug SQ prevents fractures more effectively than risedronate 35 mg PO weekly in women with severe osteoporosis [81] (industry-sponsored study) h) abaloparatide, an analog of human PTH-related protein FDA approved April 2017 for high-risk patients - recommended as option for postmenopausal osteoporosis by NICE August 2024 12) romosozumab (Evenity) conditionally recommended for women with very high risk of fracture [92] - 1 year of use maximum, follow with bisphosphonate [92] 13) estrogen no longer recommended [2,77] - premarin 0.625 mg PO QD (or other estrogen) - PremPro 0.625/2.5 if woman still has uterus - Menostar is a weekly estradiol patch [18] - estrogen attenuates osteoclast bone resorption - when prophylactically used, can prevent expected post-menopausal accelerated bone loss - when used as treatment for established osteoporosis, increases in bone mineral density of 2-4% may be seen for 1-2 years, predominantly in the spine - decreases incidence of spine fractures by 50% - effects at the hip are more modest than the spine, but a decline in hip fractures is noted - cessation of estrogen replacement therapy results in declining bone mass - tibolone is a combination of estrogen, testosterone, progestin - NOT protective if started late 14) combined estrogen plus bisphosphonate [10] 15) thiazide diuretics (HCTZ) diminish urinary Ca+2 excretion & may reduce bone loss & risk of hip fracture [15,21] RR 0.8 16) beta-blockers may diminish bone loss & reduce risk of fracture [21] RR 0.83 17) proton pump inhibitors may increase risk of hip fractures & vertebral fractures (see proton pump inhibitor) 18) comparative effectiveness [62] a) for bisphosphonates, denosumab, teriparatide, & raloxifene, treatment of 60-89 women for 1-3 years to prevent one vertebral fracture [62] b) excluding raloxifene, treatment of 50-60 women for 1-3 years to prevent 1 nonvertebral fracture [62] c) for zoledronic acid, treatment of 30 men for 2 years to prevent one vertebral fracture d) bone anabolic agents, abaloparatide & romosozumab more effective than bisphosphonates in preventing clinical & vertebral fractures [94] 19) universal measures a) reduce risk of falls 1] identify & treat sensory deficits, neurologic disease, arthritis 2] adjust doses of sedating drugs 3] gait & balance training 4] environmental measures b) increase in physical activity [7] 1] weight-bearing aerobic exercise [91]* a] walking, dancing, hiking & stair climbing are preferable exercises b] skipping, jumping, step aerobics are associated with knee & ankle injuries in older adults 2] resistance training with weights c) smoking cessation d) avoid excessive alcohol e) hip protectors of questionable benefit 20) see screening for osteoporosis * see sclerostin for mechanism of weight-bearing exercise [91] Clinical trials; - romosozumab a monoclonal antibody that binds to sclerostin & increases bone formation may be useful for treatment of osteoporosis [56] - romosozumab increases bone mineral density at the hip in bisphosphonate non-responders [79] Comparative biology: - in mice, semaphorin 3A simultaneously promotes bone formation & inhibits bone resorption [48]

Interactions

disease interactions

Related

bone mineral density (BMD) Fosamax Actonel Comparison Trial FRAX fracture risk assessment tool Heart & Estrogen/Progestin Replacement Study (HERS) osteopenia Osteoporosis Self-Assessment Tool pharmaceutical agents that cause bone loss Prevent Recurrence of Osteoporotic Fracture (PROOF) Study screening for osteoporosis Study of Osteoporotic Fractures (SOF)

Specific

HIV1/AIDS-associated osteoporosis

General

bone disease; osteopathia chronic musculoskeletal disease

Database Correlations

OMIM 166710

References

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