Resident Editor: Alfredo Aguirre, MD 

Faculty Editor: Douglas Bauer, MD

Background

• Defined as the presence of low-trauma hip or spine fracture, or very low BMD.
• The WHO uses T-score in diagnostic criteria for osteoporosis and low bone mass (previously “osteopenia”)
• Osteoporosis: lowest measured T-score < -2.5 (patient’s bone mineral density (BMD) is 2.5 standard deviations (SD) below the young adult reference mean).
• Low bone mass: lowest measured T-score between –1.0 and –2.5.
• Prevalence: 10 million Americans have osteoporosis. 50% of Caucasian women and 20% of men will experience a typical osteoporosis-related fracture (vertebral, hip, distal radius).
• Fractures result in limitation of ambulation, loss of independence, depression, and chronic pain. 20% of patients with hip fracture require long-term nursing home care.
• Fractures of the hip and spine are associated with an increased mortality rate of 10-20% and increase the risk of subsequent fracture by greater than 2 fold.

Signs and Symptoms

• Osteoporosis is asymptomatic until fracture occurs, which is why prevention is important. 
• Risk factors: postmenopausal women, advancing age, Caucasian or Asian ethnicity, previous fracture, parental history of hip fracture, low BMI, smoking, heavy EtOH use, early menopause, low calcium and vitamin D intake, falls, impaired mobility, muscular weakness, and impaired vision or balance.
• Medications that increase risk: glucocorticoids, heparin, anticonvulsants, lithium, gonadotropin releasing hormone agonists, aromatase inhibitors, depo-medroxyprogesterone, cancer chemotherapeutic drugs, cyclosporine, tacrolimus, excess thyroid hormone. Prolonged PPI use may increase fracture risk.
• Diseases associated with increased risk of osteoporotic fracture: chronic medical conditions (renal insufficiency, chronic liver disease, sickle cell disease, post-transplant); nutritional deficiencies (vitamin D deficiency, eating disorder, EtOH abuse); endocrine disorders (DM, hypercortisolism, hyperparathyroidism, hyperthyroidism, hypogonadism, hyperprolactinemia); inflammatory diseases (rheumatoid arthritis, SLE, HIV disease); malabsorption (IBD, celiac disease, CF, pancreatic insufficiency, gastric bypass); malignancies (myeloma); collagen disorders (Marfan, osteogenesis imperfect, Ehlers-Danlos).

Evaluation

• Diagnosis of osteoporosis: 
  • Low-trauma (fragility) fracture of spine or hip regardless of BMD. Low-trauma can include fall from standing height.
  • T score ≤-2.5 at L-spine, femoral neck, total hip and/or distal radius.
• Approach to screening:

• Evaluate osteoporosis risk factors. Age, previous history of fracture, and BMD are the strongest predictors of fracture risk. 
• Perform DEXA: Screening DEXAs include total hip, femoral neck and lumbar spine measurements. Measure distal radius if arthritis or surgical changes interfere with spine or hip readings.
  • For pre-menopausal women and men <50, Z-scores are used (value <-2.0 indicates low BMD for patient’s age/race/sex).
  • DEXA indicated for following:
    • Women age 65 or older
    • Postmenopausal women with low-trauma fracture or radiographic osteopenia
    • Men and women with secondary osteoporosis. Age of screening depends on risk. 
      • Ex. Any patient on chronic high dose steroids (≥ 5mg/day of prednisone for at least 3 months)
      • Men age 70 or older
      • Men and women ≥50 with osteoporosis risk factors
    • Every 2 years for T-scores -2.0 to -2.49, ongoing risk factors for bone loss or those undergoing medical therapy.
    • Every 3-5 years for women ≥65 with T-scores -1.50 to -1.99 without ongoing risk factors.
    • Every 10-15 years for women ≥65 with T-scores of -1.49 or better without ongoing risk factors.
• Calculate FRAX Score in all patients with osteopenia: Calculates the 10-year probability of hip fracture and major osteoporotic fracture. (http://www.shef.ac.uk/FRAX). Tool developed in treatment-naïve patients. 
• Conduct lab evaluation:
  • Initial lab evaluation: Vitamin D and calcium, phosphorus, CBC, chemistries, TSH. 
  • Other lab tests if clinically indicated: LFTs, albumin, PTH, estradiol/testosterone, LH/FSH, prolactin, celiac screen, homocysteine, SPEP/UPEP, 24hr urine calcium, 24hr urine cortisol, iron studies, RF, ESR. 

Treatment

• For all women and men >50: Adequate intake of calcium (1000-1200mg/day in diet and supplements) and vitamin D (1000 IU/day). Also encourage weight bearing exercise, fall prevention, smoking cessation and drinking alcohol in moderation. 
• Pharmacologic therapy indicated in the following: 
  • Patients with diagnosis of osteoporosis.
  • Patients with osteopenia and high fracture risk: FRAX score ≥3% for 10-year hip fracture risk or ≥20% for major osteoporosis-related fracture risk..
• Ensure that all patients are Vitamin D replete prior to starting bispshosphonate therapy to prevent hypocalcemia. Recommended level is >20 ng/ml.
• Bisphosphonates: First line treatment.
  • Alendronate (70mg/week PO) and risderonate (35mg/week PO) have been shown to reduce vertebral, hip and other non-spine fracture. Taken upright on empty stomach in AM with full glass of water 30 min before other meds/food.
  • Ibandronate has been shown to reduce vertebral fracture only. Taken orally once monthly or IV. 
  • Zolendronate has been shown to reduce vertebral, hip and other non-spine fracture. 5mg IV once yearly for patients who cannot tolerate oral bisphosphonates or when adherence uncertain.
  • Use with caution in CKD. Do not use bisphosphonates in patients with a CrCl<35mL/min, esophageal disease (achalasia).
  • Adverse effects: Esophagitis, bone/joint/muscle pain, hypocalcemia.
  • Rare adverse effects: Osteonecrosis of the jaw (seen mostly in cancer patients treated with high-dose IV formulations and in patients with dental issues) and atypical femoral fractures (AFF).
  • Bisphosphonates are not recommended in women of childbearing age without adequate contraception.
  • “Drug holidays”- recommended for patients receiving bisphosphonate therapy, though optimal timing and duration has not been defined. For mild osteoporosis consider drug holiday after 5 years of oral therapy, 3 years of IV. For those with severe disease (T<-2.5 after treatment, any history of hip or spine fracture) consider drug holiday after 10 years of therapy.
• PTH analogs: Teriparatide and (recently) abaloparatide. Reduce risk of vertebral and non-vertebral fracture. Recommended for patients with very high fracture risk or who have failed prior treatments. Taken as daily SC injection. Causes nausea, leg cramps, rarely hypercalcemia. Teriparatide has black box warning for osteosarcoma (avoid in Paget’s disease, h/o XRT to bone). 
• Denosumab: A human monoclonal antibody that blocks RANK ligand, leading to osteoclast inhibition. Reduces vertebral, non-vertebral and hip fracture risk. Recommended for patients with high fracture risk and patients with CKD. Given as a 60mg SC injection once every 6 months. Not recommended in ESRD (hypocalcemia); osteonecrosis of the jaw and atypical fractures reported (rare).
• Raloxifene: Reduces the risk of vertebral fracture only. Has an increased risk of VTE and hot flashes, but reduces the risk of breast cancer. Used in patients at high risk of breast cancer or unable to tolerate a bisphosphonate. 
• Estrogen or HRT: Prevents vertebral, hip and other non-spine fracture, but no longer a first-line treatment because of increased risk of breast CA, CVA, VTE, and CAD.
• Nasal calcitonin: Weak anti-fracture efficacy and modest effect on BMD. Daily intranasal spray. Not recommended.

Monitoring Therapy

• BMD monitoring during treatment is controversial, and ACP guidelines recommend against.  May be helpful after 3-5 years to inform drug holiday.

When to refer

• For severe osteoporosis or for patients that continue to fracture on bisphosphonate therapy.
• For further evaluation of some secondary causes of osteoporosis.

References

Camacho, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis — 2016. Endocr Pract. 2016;22:Suppl4;1-42

Cosman, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014; 25(10): 2359–2381.  

Cummings et al, FREEDOM Trial Group, “Denosumab for prevention of fractures in postmenopausal women with osteoporosis.” N Engl J Med. 2009;361(8):756.

Black, et al. Postmenopausal Osteoporosis. N Engl J Med 2016; 374:254-262.

Roux, et al. Addressing the crisis in the treatment of osteoporosis. Nature Reviews Rheumatology 14, 67–68 (2018)