osteoporosis
OSTEOPOROSIS
Osteoporosis is the progressive, systemic skeletal disease characterized by decreased bone mass and micro-architectural deterioration of bone tissue leading to increased bone fragility and susceptibility to fractures.
The more risk factors (eg history, of fracture, advanced age, comorbidities, impaired vision) that are present, the greater the risk of fracture.

Principles of Therapy

  • Choice of drug will depend not only on its capacity to increase BMD but also on reducing spine and hip fracture
  • Therapy should be initiated without delay (2 weeks or more after a hip fracture) based on fracture risk in patients with recent fractures to prevent more fractures
    • Fracture within the past 2 years is a better predictor of imminent fracture risk (fracture within the next 2 years) than a distant fracture (>5 years ago)
  • Postmenopausal women and men ≥50 years old with the following should be considered for treatment:
    • Low-trauma hip, vertebral or wrist fracture
    • T-score of ≤ -2.5 at the femoral neck, total hip, lumbar spine, or 33% radius by DXA
    • Low bone mass (T-score between -1.0 and -2.5 at the femoral neck, lumbar spine, total hip, or 33% radius by DXA, osteopenia) and 10-year FRAX™ fracture probability of ≥3% at the hip or ≥20% for major osteoporosis-related fracture at 10 years
  • If FRAX™ is not available, treatment may be initiated in patients >65 years old with several risk factors and who are at high risk of osteoporosis
  • On discontinuing glucocorticoids, treatment in continued similar to non-glucocorticoid osteoporosis for those with confirmed or high risk for osteoporosis
  • Switching from antiresorptive therapy [bisphosphonates, Denosumab, hormonal therapy (HT), selective estrogen receptor modulators (SERM), Strontium ranelate] to bone formation (Teriparatide, Abaloparatide) is considered in the following:
    • Postmenopausal women with osteonecrosis of the jaw or atypical femoral fracture on antiresorptive therapy
    • Postmenopausal women with recurrent vertebral fractures due to osteoporosis
    • Postmenopausal women at high fracture risk and on long-term potent antiresorptive therapy and sustaining fractures

Pharmacotherapy

Bisphosphonates
  • 1st-line of treatment for osteoporotic patients and patients receiving glucocorticoids with osteoporotic fractures or established osteoporosis
  • Inhibits osteoclast activity and potent inhibitors of bone resorption
  • Have no effect on menopausal symptoms
  • Evaluate efficacy of treatment after 3 years on IV therapy and 5 years on oral therapy
    • If ineffective (ie declining BMD or recurrent low-trauma fracture), exclude secondary causes of osteoporosis and/or noncompliance
  • A bisphosphonate holiday may be given to patients on oral therapy after a stability of 5 years or on intravenous therapy after a stability of 3 years in low to moderate-risk patients
    • American Society for Bone and Mineral Research (ABSMR) Task Force on Long-Term Bisphosphonates has suggested bisphosphonate holiday for low-moderate risk and switching to another therapy or continuing bisphosphonate in those at high risk
    • A bisphosphonate holiday is defined as temporary discontinuation of bisphosphonate for up to 5 years or longer depending on the BMD and clinical circumstances of the patient; reassessment of fracture risk is done at 2- to 4-year intervals and osteoporosis therapy is re-initiated earlier than 5-year suggested maximum if there is significant reduction in BMD or an intervening fracture
  • Bisphosphonate therapy is associated with possible risk of osteonecrosis of the jaw and atypical femur fracture
  • Should not be given as initial therapy in patients with esophageal diseases, history of failed compliance with medication intake instructions and those with chronic renal disease
Alendronic acid
  • Used in the prevention and treatment of postmenopausal osteoporosis
    • Increases bone mineral density (BMD), reduces risk of hip, spinal and non-vertebral fractures
  • Approved for the treatment of osteoporosis in men
    • Increases bone mineral density (BMD), reduces risk of spinal fractures
  • Approved for the prevention (primary and secondary) and treatment of glucocorticoid-induced osteoporosis (GIOP) in men and women
    • Reduces risk of spinal fractures
Etidronic acid
  • Used in the prevention and treatment of postmenopausal osteoporosis
    • Increases bone mineral density (BMD), reduces vertebral fractures
    • An observational study shows reduction in non-vertebral and hip fractures
  • Used in the prevention (primary and secondary) and treatment of glucocorticoid-induced osteoporosis (GIOP)
    • Reduces risk of spinal fractures
Ibandronic acid
  • Used in the prevention and treatment of postmenopausal osteoporosis
    • Increases bone mineral density (BMD), reduces risk of vertebral fractures 
Risedronic acid
  • Approved for the prevention and treatment of postmenopausal osteoporosis
    • Increases bone mineral density (BMD), reduces risk of hip, spinal and non-vertebral fractures
  • May be used in the treatment of osteoporosis in men
    • Increases bone mineral density (BMD)
    • Reduces the risk of hip fractures in men with stroke and concomitant osteoporosis
    • Reduces the risk of spinal fractures in men with idiopathic osteoporosis
  • Used in the prevention (primary and secondary) and treatment of glucocorticoid-induced osteoporosis (GIOP) in men and women
    • Reduces risk of spinal fractures
Zoledronic acid
  • Used in the prevention and treatment of postmenopausal osteoporosis
    • Increases bone mineral density (BMD), reduces the risk of vertebral, non-vertebral and hip fractures
  • Used in the prevention (primary and secondary) and treatment of GIOP 
  • Also indicated in the prevention of new clinical fractures in patients who recently had a low-trauma hip fracture
  • Also recommended in the prevention and treatment of osteoporosis in women expected to be on glucocorticoid treatment for at least 12 months
  • A drug holiday may be given to patients on IV therapy following 3 yearly doses in moderate-risk patients and 6 yearly doses in high-risk patients
Hormonal Therapy1(HT)
  • Primarily indicated for treatment of moderate-severe menopausal symptoms (eg vaginal atrophy, vasomotor symptoms) in healthy perimenopausal or menopausal women and for the prevention of osteoporosis
    • Increases bone mineral density (BMD) of lumbar spine and femoral neck, reduces risk of vertebral, non-vertebral and hip fractures
    • Physician and patient must consider risk versus benefit before using hormonal therapy (HT) as 1st-line treatment for the prevention of osteoporosis in women with menopausal symptoms; other treatments should be considered first
  • When used for treatment of osteoporosis, hormonal therapy (HT) should be administered in its lowest effective dose for the shortest duration due to possible risks; abrupt treatment withdrawal is not recommended
    • Current data suggests that symptom recurrence is similar when hormonal therapy is either tapered or abruptly discontinued
  • May be considered in women 50-59 years of age or postmenopause <10 years
  • Estrogen is not recommended for prevention of fractures in the absence of menopausal symptoms

1For details on hormonal therapy in menopausal women, please see Menopause and Hormone Therapy Management Chart. 

Parathyroid Hormone (PTH)
Teriparatide [Recombinant human Parathyroid Hormone (PTH) (1-34)]
  • Approved for the treatment of postmenopausal osteoporosis and for men at high risk for fractures and with severe osteoporosis or osteoporosis not responsive to other anti-osteoporosis therapy
    • Increases bone mineral density (BMD), reduces risk of spinal and non-vertebral fractures
  • Has been approved for use for a maximum of 24 months
  • Indicated to increase bone mineral density (BMD) in men with primary or hypogonadal osteoporosis at risk of fracture
  • May be used in the prevention and treatment of glucocorticoid-induced osteoporosis (GIOP)
    • Increases bone mineral density (BMD), reduces vertebral fractures
  • Stimulates new bone formation in cortical and trabecular bone
  • Has anabolic effects on bones
  • May follow treatment with a bisphosphonate or other antiresorptive agents to maintain or increase bone mineral density (BMD)
  • A trial has shown that Teriparatide reduces fractures more than Risedronate
Abaloparatide
  • Newly approved human PTH-related peptide (PTHrP) analog indicated for the treatment of postmenopausal osteoporosis in women at high risk for fractures and in patients unresponsive or intolerant to other anti-osteoporosis therapy
  • Studies showed reduction in vertebral and nonvertebral fractures with long-term treatment
Receptor Activator of Nuclear Factor Kappa-B (RANK) Ligand (RANKL)/RANKL Inhibitor
Denosumab
  • Approved for the treatment of osteoporosis in men and postmenopausal women at high risk of fracture
    • Reduces the incidence of vertebral, hip, and non-vertebral fractures and improves bone mineral density (BMD)
  • Also used for the treatment of bone loss in women with breast cancer on aromatase inhibitor treatment, bone loss in men receiving prostate cancer treatments who are at high risk for fracture, and for increasing bone mass in men at high risk of fracture
  • Inhibits formation, function and survival of osteoclasts leading to a decreased bone resorption
  • A drug holiday is not recommended to patients on Denosumab therapy
  • Postmenopausal women with osteoporosis and are on Denosumab should be reassessed every 5-10 years for fracture risk
  • Administration should not be delayed or discontinued without subsequent antiresorptive therapy (eg bisphosphonates, HT, SERM) administered to prevent rebound in bone turnover and to decrease the risk of rapid BMD loss and increase the risk of fracture
Selective Estrogen Receptor Modulators (SERM) 
Raloxifene
  • Considered as treatment following poor tolerability with 1st-line agents
  • Approved for both prevention and treatment of postmenopausal osteoporosis
    • Increases bone mineral density (BMD), reduces risk of vertebral fractures but not non-vertebral fractures
  • May be preferred treatment in women <65 years old without a hip fracture history
  • Binds to estrogen receptors in target organs to produce various estrogenic effects
  • Reduces the risk of invasive breast cancer in postmenopausal women with osteoporosis
Lasofoxifene
  • A 3rd-generation SERM approved for the prevention and treatment of postmenopausal osteoporosis in Europe with pending approval in the US
  • Selectively binds to estrogen receptors thereby reducing the production and lifespan of osteoclasts, stimulation of osteoblast activity, with additional effects on calcium homeostasis
  • Studies showed reduction in vertebral and nonvertebral fractures with long-term treatment

Bazedoxifene

  • Approved in Germany, Japan, Israel and Sweden as monotherapy for prevention of osteoporosis
Strontium ranelate
  • Used for treatment of severe osteoporosis in postmenopausal women for whom there are no other osteoporotic treatments due to eg contraindications or intolerance
    • Reduces the risk of vertebral and non-vertebral fractures
    • Reduces the risk of hip fractures in women ≥74 years of age with bone mineral density (BMD) T-score < -3
    • Prevents bone loss and vertebral fractures in women with osteopenia
  • Considered as an oral alternative for patients with contraindications to or are intolerant of oral bisphosphonate therapy
  • Stimulates the formation of new bone tissue and decreases bone resorption as proven in in vitro and experimental studies in animals and long-term clinical studies
  • Assessment of risk for cardiovascular disease development should be done prior to treatment and should be monitored every 6-12 months
    • Treatment should be stopped if patient develops cerebrovascular disease, ischemic heart disease, uncontrolled hypertension or peripheral arterial disease
Calcitonin
  • 32 amino acid hormone secreted by C cells of the thyroid gland
  • Approved for the treatment of osteoporosis in women who have been postmenopausal for >5 years and intolerant of bisphosphonates, hormone-based therapies, selective estrogen response modulators, Tibolone, Abaloparatide or Teriparatide, or when these treatment options are not appropriate
    • Increases bone mineral density (BMD), reduces risk of spinal fractures
  • In glucocorticoid-induced osteoporosis (GIOP), is considered only for patients unable to tolerate oral or IV bisphosphonates or Teriparatide
  • Inhibits osteoclast activity and decreases bone resorption
  • Has no effect on menopausal symptoms
  • Has analgesic effect for acute pain relief in osteoporotic fractures
  • Consider benefits of therapy versus risks including potential risk for malignancy with long-term use; limit use to <6 months
Activated Vitamin D
  • Used in the treatment of postmenopausal osteoporosis
    • Improves bone mineral density (BMD) and reduces vertebral fracture rate
  • Used in the prevention (primary and secondary) and treatment of glucocorticoid-induced osteoporosis (GIOP)
    • Bone mineral density (BMD) improvement but no data to confirm reduction of vertebral fractures
  • Regulates the homeostasis of calcium and bone formation
  • Limit concurrent use of calcium to <800 mg to decrease the risk of renal stone disease and hypercalcemia
Tibolone
  • A selective tissue estrogenic activity regulator (STEAR)
  • Approved for the prevention of postmenopausal osteoporosis
    • Data have demonstrated a reduction in vertebral fracture and improvement of bone mineral density (BMD)
  • Synthetic agent which has weak estrogenic, progestogenic and androgenic properties
  • Reduces menopausal symptoms but it does not stimulate uterine or breast tissues
Testosterone
  • Suggested in men at borderline high risk for fracture who have serum testosterone levels <200 ng/dL that is accompanied by signs or symptoms of androgen deficiency or organic hypogonadism
  • Also suggested in men at high risk for fracture with testosterone levels <200 ng/dL who lacks standard indications for testosterone therapy but who have contraindications to approved pharmacological agents for osteoporosis
  • Many studies have demonstrated that replacement therapy increases bone mineral density (BMD) in men with hypogonadism, however, effects on fracture reduction are unclear
Combination Therapy
  • Combination of a bisphosphonate with  a non-bisphosphonate can provide additional small increase in BMD when compared with monotherapy
  • A better BMD response is seen with Denosumab and Teriparatide combination therapy than either agent alone, though there are no available fracture data
  • SERM Bazedoxifene combined with conjugated Estrogen may be considered for the prevention of postmenopausal osteoporosis in patients where other therapies are not appropriate
  • Added cost and potential increased side effects should be weighed against potential gains
Other Agents
Sodium fluoride (Na fluoride)
  • Stimulates bone formation
  • Further studies are needed to prove the efficacy of Sodium fluoride in reducing fracture risk
Genistein
  • A tyrosine kinase inhibitor used in the management of menopausal symptoms
  • Further studies are needed to prove its benefit on bone health and fracture risk

Non-Pharmacological Therapy

Nutrition
Calcium (Ca) and Vitamin D
  • Prevention of osteoporosis
    • Lifelong intake of adequate calcium (Ca) is associated with higher peak bone mass which reduces the risk of osteoporosis/fracture in later life
    • Recommended calcium (Ca) intake: 1000 mg/day for men 50-70 years old; 1200 mg for women ≥51 years old and men ≥71 years old
    • The main sources of calcium (Ca) are dairy products; vegetables (eg broccoli, cabbage) are also a good source
    • Vitamin D helps in intestinal calcium (Ca) absorption, bone mineralization, and enhance response to bisphosphonate therapy
    • Recommended Vitamin D intake for patients >50 years of age: 800-1000 IU/day
      • Higher doses may be needed in patients with malabsorption, obesity, older individuals, transplant patients
    • 25 (OH) D blood levels of >20 ng/mL is a good index for adequate bone health and Vitamin D stores
    • The main sources of Vitamin D are from sun exposure (>15 minutes/day), fortified milk, cereals, egg yolks, salt water fish and liver
  • Treatment of osteoporosis
    • Calcium and Vitamin D supplements may be administered as adjunct to other drug therapies in the treatment of osteoporosis
    • Help to increase bone mineral density (BMD) and may reduce fracture risk in men and postmenopausal women with osteoporosis
  • Glucocorticoid-Induced Osteoporosis
    • Recommended for prevention and treatment
    • Has been shown to reduce bone loss
Good General Nutrition
  • Excessive dieting and low body weight is associated with increased risk of fracture
    • Recommend BMI ≥19 kg/m2
  • Maintenance of adequate energy and protein intake (US RDA 0.8 g/kg) is important as well as consuming a balanced diet
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