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Osteoporosis

GIO 

Clinical Problem: 
Approximately 1% of all adults and 3% of adults older than 50 years of age receive glucocorticoids and fracture is the most common serious and preventable adverse event 

The risk of fracture increases with age, dose and duration 

Vertebral fractures are the most common fractures associated with glucocorticoids; the risk of vertebral fracture increases within 3 months after initiation of treatment and peaks at 12 months.

The relative risk of clinically diagnosed vertebral fracture doubles and the risk of hip fracture increases by approximately 50% among patients who receive 2.5 to 7.5 mg of prednisolone daily.

In a study with a follow-up of 6 months to 10 years, glucocorticoids taken at very high doses i.e among adults who received 30 mg of prednisolone per day with cumulative doses of at least 5 g, the risk of vertebral fracture increased by a factor of 14 and the risk of hip fracture increased by a factor of 3. 

The intermittent use of high-dose glucocorticoids with cumulative doses of 1 g or less had less effect on the risk of fracture whereas the use of high-dose inhaled glucocorticoids (≥1000-μg fluticasone dose equivalents) for more than 4 years increased the risk of fracture slightly (relative risk, 1.10; 95% confidence interval [CI], 1.02 to 1.19).

Pathophysiology



Glucocorticoids have direct and indirect effects on bone remodeling.

Direct Impact:
  1. Osteoclast: Bone loss results from increases in expression of receptor activator of nuclear factor-κB ligand (RANKL), which lead to increases in the number of bone-resorbing osteoclasts.
  2. Osteocyte: increased oxtecyte apoptosis induces osteolysis, which results in an early increased risk of fracture even before bone mineral density decreases. 
  3. Osteoblast: Bone formation also decreases early in glucocorticoid treatment because of a decrease in osteoblast recruitment and accelerated apoptosis. 
Indirect Impact that also predispose patients to an increased risk of fracture include 
  1. Muscle: reduced muscle mass leading to an increased risk of falls, 
  2. Ca: decreases in renal calcium resorption and
  3. Sex homrones: decrease in levels of sex hormones
  4. PTH: alterations in parathyroid hormone pulsatility
The risk of fracture rapidly decreases when glucocorticoids are discontinued. Within 6 month, improvement in BMD was noted in prospective study on dincontinuation of steroid. A large retrospective study showed an increased risk of a major osteoporotic fracture among patients with recent prolonged glucocorticoid use but not among those with intermittent or past use of these agents

FRAX Score in GIO 
FRAX  estimates of the 10-year risk of major osteoporotic fracture and hip fracture among patients who are at least 40 years of age
Although the risk of fracture can be calculated when the bone mineral density T score is not available, bone mineral density testing is recommended for people who receive glucocorticoids and are at least 40 years of age, since this testing improves the accuracy of FRAX estimates 
Limitation:
  1. When glucocorticoid use is added as a risk factor in the FRAX tool, the fracture estimates reflect the risk associated with prednisone at a dose of 2.5 to 7.5 mg per day; however, analysis of data from the U.K. General Practice Database suggests that among patients who receive more than 7.5 mg of prednisone daily, the FRAX-predicted risk of major osteoporotic fracture has to be increased by 15% and the risk of hip fracture has to be increased by 20%. However, among patients who receive very high doses of prednisone (>30 mg per day or cumulative doses to >5 g per year), this adjustment may underestimate the risk of fracture. 
  2. FRAX score calculation is the use of bone mineral density at the hip instead of at the lumbar spine, since glucocorticoids have the greatest negative effect on trabecular bone in the spine
  3. Cannot be used for age less than 40 years of age
Patient with Rheumatology Illness associated with increased risk of osteoporosis 




OSTEOPENIA

WHO Fracture Risk Assessment Tool 
69 yo F is seen for Osteopenia. Patient has a history of breast cancer treated 3 years back. ER, PR status is not known. How should you treat this patient along with Ca, and Vitamin D supplementation to prevent Osteoporosis (FRAX score is > 5 for Hip fracture and 12 for Major Fracture). 

1. Start Ibandronate (Boniva)
2. Start Denosumab (Prolia) 60 mg) is administered by subcutaneous injection once every six months
3. Start Raloxifen (Evista).
4. Start Alendronate (fosamax). 
5. Start Teriperatide (Forteo) dose of PTH 1-34 is 20 mcg/day. A multi-dose prefilled pen (containing 28 doses) is available. It is administered via subcutaneous injection into the thigh or abdominal wall. The initial dose should be administered in a setting where the patient can sit or lay flat, if symptoms of orthostatic hypotension occur. Due to the potential risk of carcinogenicity, PTH treatment should be given for a maximum of two years
6. Start Risedronate (actonel) 

Ans: Given history of Breast cancer, Raloxifen is useful for the prevention of invasive breast cancer. 

Note: Vitamin Supplementation of 400-800 IU/day leads to appropriate level of vitamin D, even as much as near 70. 


Re: Ca and Vitamin D and GIO 
  1. A Cochrane meta-analysis estimated that the bone mineral density (measured in grams per square centimeter) at the lumbar spine was significantly higher among patients who received calcium and vitamin D supplementation than among those who received placebo (weighted mean difference, 2.6%; 95% CI, 0.7 to 4.5).
  2. Randomized trials have shown that calcium and vitamin D supplementation prevented decreases in bone mineral density in the spine during long-term use of low-dose prednisone (mean dose, 5 mg per day) but did not completely prevent bone loss in patients who were beginning to receive high-dose treatment (mean dose, 23 mg per day).
  3. Calcium alone is not effective in preventing bone loss,19 and studies of the effect of calcium and vitamin D on rates of fracture among patients who receive glucocorticoids are lacking.




GIO 









WHOM TO TREAT: ACR: 

  1. all adults with a previous fragility fracture; 
  2. adults ≥40 yr with BMD T score of −2.5 or less or 
  3. adults  ≥40 yr with  FRAX risk ≥20% for major osteoporotic fracture or ≥3% for hip fracture§;  

(after increasing the risk by 15% and 20%, respectively, for a prednisone dose >7.5 mg daily).   Case from NEJM  has a risk of 16% and 3.2%. Increase of 15% will lead to 18.4%, and Increase of 20% leads to  3.8 % 

Discussion notes: On the basis of her bone mineral density T score and use of high- dose prednisone, the FRAX 10-year risk of major osteoporotic fracture is 18% and the risk of hip fracture is 3.8% (after increases of 15% and 20%, respectively, in the risk because of use of high-dose prednisone).


  1. consider in adults ≥40 yr with FRAX risk 10 to 19% for major osteoporotic fracture or >1 to 2.9% for hip fracture, adults
  2. <40 yr  (no role of FRAX) with 
    1. BMD T score below −3 and >7.5 mg of prednisone daily, 
    2. adults with >10%/yr bone loss at hip or spine, and 
    3. adults ≥30 yr taking very-high-dose glu- cocorticoids (≥30 mg daily) or high cumulative dose of > 5 gm/yr 

APPROVED FOR GIO: ARZTD - R  (Arizona Touch Down - right?)

Bisphosphonates: 

  1. In a 2016 Cochrane review that included 12 randomized trials and involved 1343 participants, participants who received bisphosphonates had a 43% (95% CI, 9 to 65) lower risk of new vertebral fractures than participants who received calcium, vitamin D, or both; 
  2. the estimated number needed to treat to prevent one glucocorticoid-induced vertebral fracture was 31.
  3. In patients who received bisphosphonate treat- ment for osteoporosis for 3 to 5 years, serious adverse events, including atypical femoral frac- tures and osteonecrosis of the jaw, have been reported to be rare (<0.01% and <0.001%, re- spectively).
Teriperatide 
  1. In a trial involving 428 patients who were receiving glucocorticoids, patients received either teriparatide or alendro- nate for 36 months. Teriparatide was associated with greater increases in bone mineral density at the spine than alendronate (11% vs. 5.3%, P<0.001) and a lower rate of radiographic verte- bral fractures (1.7% vs. 7.7%, P = 0.007); however, there was no significant difference in rates of nonvertebral fracture between the two treatment groups.
  2. Hypercalcemia occurred in 21% of patients in the teriparatide group, as compared with 7% of those in the alendronate group.
  3. However, bone loss and fractures occur rapidly after teriparatide is discontinued; therefore, after discontinuation, an antiresorptive agent such as bisphosphonate or denosumab should be initiated.
  4. Initial treatment with an anabolic agent such as teriparatide or abaloparatide, followed by an antiresorptive agent, may be considered for treatment of severe osteoporosis (bone min- eral density T score below −2.5 in patients with a history of fracture). REASON WHY TO DO DEXA irrespective of dose and duration of Steroid . Also, note Denusumab has the same problem and increased risk of fracture if patient had previous fracture. So, patients with previous vertebral fracture, Bisphosphonates are better. 
Denosomab
  1. Denosumab inhibits bone resorption by binding to RANKL and interfere with development of osteoclasts 
  2. A noninferiority trial comparing denosumab with risedronate in patients who were beginning to receive glucocorticoids and in those who had received these agents long-term showed superiority of denosumab with respect to increases in bone mineral density at the spine at 12 months and noninferiority with respect to rates of fracture.36 
  3. Some but not all studies have shown a higher risk of infection with denosumab than with bisphosphonates. Given the limited available safety data, denosumab is generally not recommended as the first- line treatment in patients taking multiple immunosuppressive drugs or a biologic treatment.
  4. At doses of denosumab that are used to treat osteoporosis, the risks of osteonecrosis of the jaw (0.001 to 0.15%) and atypical fractures are low.32 
  5. However, rates of vertebral fracture in- crease rapidly after denosumab is discontinued, especially among patients with a previous verte- bral fracture, and an alternative antiresorptive therapy is recommended after discontinuation.
  6. Hypocalcemia and Vit D deficiency must be treated before use of Denosumab

Raloxifene is approved by the Food and Drug Administration for the prevention and treatment of glucocor- ticoid-induced osteoporosis in postmenopausal women. (per  NEJM 2019)

Osteoporosis/Bone Disease

Mechanisms of Anabolic Therapies for Osteoporosis NEJM 2007


Bisphosphonates for the prevention and treatment of osteoporosis BMJ 2015

Summary 
1.5 M fractures / yr in US
Disease is characterized by Skeletal fragility and micro architectural deterioration. 
300K hip fractures / yr in US 
40 mil women with low BMD
Hip and Spine Fractures: Increased risk of death 
Overview
Goal: Prevention of future fractures
Try to define absolute risk for an individual 
Identify high risk patients including prior fractures, 
DM itself is a risk for osteoporosis
Smoking: Linked to low BMD
Excess Alcohol: Linked to increased risk of fall 

Ca and Vit D: Efficacy is controversial 
Daily supplementation and not intermittent supplementation may have modest reduction of fall 
Ca: 800 - 1000  mg / day
Vit D : 600-800 IU / day 
 

Atypical Femur Fracture Risk versus Fragility Fracture Prevention with Bisphosphonates NEJM 2020


Coresspondance and reply to above article 

However, most of the published clinical trials have shorter observation periods (i.e., 1 to 4 years), and we have little information on longer-term use. In the study by Black et al., the risk of atypical femur fracture among the patients who received alendronate for 5 to 8 years was approximately 20 times as high as that in patients who received the drug for less than 3 months.

A problem with this study is that 78.1% of the patients were treated for 5 years or less. An analysis that includes all the patients does not reveal the clinical picture of long-term administration. We would like the authors to present an analysis of bisphosphonate administration for 5 years or more and to share the results of that analysis with respect to safety.

Reply: 

Black et al. present a model of hip fractures that were prevented by the use of bisphosphonates in which the incidence of hip fracture in untreated women was derived from a cohort that was studied more than 20 years ago and that included women older than 67 years of age who had a bone mineral density (BMD) T-score of less than −2.5. A biased estimate may have resulted, because in the study by Black et al., 40% of the women who received bisphosphonates were younger than 65 years of age. The authors do not report the BMD of these women, but another recent study involving women from Kaiser Permanente Southern California who had used bisphosphonates for at least 3 years showed an average BMD T-score of only −2.2.1 Furthermore, the model that was used in the study by Black et al. assumed a constant relative risk reduction “beyond the randomized trial lengths of 3 to 4 years.” However, in the randomized extension study of alendronate, the incidence of clinical fracture was the same among the women who discontinued alendronate at 5 years as it was among those who continued for 10 years, even in those with a T-score below −2.5.2 Therefore, if women stop taking bisphosphonates after 5 years of therapy, they will have the same protection from hip fracture as those who continue therapy until 10 years, but their incidence of atypical fracture will be lower.


Drugs: 2 main mechanism of action 
  • Anti-resorptive : 5 classes of medications have antiresorptive properties 
    • Bisphosphonates
    • Denosumab (Prolia)
    • Estrogen 
    • SERM
  • Anabolic : 
    • Teriperatide
    • Romosozumab
3 Medications have only vertebral fracture risk reduction but note this is different in GIO 
  • Ibandronate
  • SERM (Raloxifene)
  • Calcitonin
1 medication has Vertebral, Non-vertebral fracture reduction BUT HIP is NOT Defined
  • Teriperatide
  • Question
    • 95 yo M patient with Pagets disease has ORIF after R Hip fracture. What do you give for the treatment?
      • 1. Teriperatide
      • 2. Alendronate
        • Answer: Alendronate. 
        • Teriperatide is wrong choice for 2 reasons.
          • 1. It is an anabolic drug with risk of osteosarcoma especially in patients with Pagets disease. 
          • 2. There is no Data of use of Teriperatide when used for prevention of Hip Fracture. 
REST  has vertebral, Non-vertebral, and HIP fracture reduction 

3 Medication are used for prevention
  • Bisphosphonates
  • SERM
  • Estrogen 

Postmenopausal Osteoporosis NEJM 2016

For prevention of GIO, only 2 bisphosphonates are used. Risedronate, and Zoledronic Acid. 
For treatment of osteoporosis in MEN, Ibandronate is NOT used
For recurrent fracture, only Zoledronic acid is used. 

Controversies: Questions of concern from table below compared to NEJM table above. 
Risedronate for Hip Fracture prevention ??
Alendronate for Non-vertebral fracture ??

??? Is alendronate approved for GIO prevention? 

By ARZ-TD R? it is. Perhaps after 2015?

Bisphosphonates for the prevention and treatment of osteoporosis BMJ 2015








Osteoporosis: now and the future Lancet 2011



52 yo F with Scleroderma, Raynauds, B12 deficiency is seen for chronic back pain. Patient was diagnosed of vertebral compression fracture. Diagnosis of Steroid induced Osteoporosis was made. Patient was on Alendronate for osteoporosis in the past. DEXA results are as below. CXR shows recurrent vertebral fracture. GFR is 25.  
Vitamin D is 15. TSH is normal. What is the best treatment strategy in addition to Ca, Vitamin D supplementation? 
1. Start Ibandronate 
2. Start Denosumab 
3. Test for celiac disease.
4. Treat with Alendronate. 
5. Treat with Teriperatide 
6. 3 and 5 


Note: Ans. 
Teriperatide address the decreased bone formation affect of steroids by decreasing the osteoblast apoptosis. Anti-resorptive medication (bisphosphonate do not have this advantage as they work on osteoclast predominantly). 

Also, per NEJM 2019: Initial treatment with an anabolic agent such as teriparatide or abaloparatide, followed by an antiresorptive agent, may be considered for treatment of severe osteoporosis (bone min- eral density T score below −2.5 in patients with a history of fracture). 

Alendronate is not the write answer for it failed to work in the past, but also is not used for recurrent vertebral fracture. 
Ibendronate (only used for PMO). Ibandronate is used in very limited set up. (see above in the table) 

Vitamin D deficiency must be treated before use of Denosumab. Denosumab also does not address decreased bone formation effect of steroids as it acts on osteoclasts. 

Zoledronic acid could be used, however same limitation of anti-resorptive medications in a patient with GIO
Note: 
Alendronate is not used for the prevention of GIO. Risdronate, and Zoledronic acid can be used. 



52 yo F with Scleroderma, Raynauds, B12 deficiency is seen for chronic back pain. Patient is on chronic steroid use. What is the best to prevent osteoporosis.
Ans: Resedronate or Zoledronic acid. Note Ibandronate (Boniva) and Alendronate (fosamax) are not best for prevention of GIO ???

52 yo F with Scleroderma, Raynauds, B12 deficiency is seen for chronic back pain. Patient is on chronic steroid use. DEXA including hand is done. Shows osteoporosis of wrist. What is the best bisphonate to treat osteoporosis.
Ans: Resedronate or Zoledronic acid. Note. Like in case of GIO prevention Ibandronate (Boniva) and Alendronate (fosamax) are not best for treatment of non-vertebral osteoporosis. ???

52 yo F with Scleroderma, Raynauds, B12 deficiency is seen for chronic back pain. Patient is on chronic steroid use. DEXA including hand is done. Shows osteoporosis of wrist and hip. What is the best bisphonate to treat osteoporosis.
Ans: Zoledronic acid. Note. Like in case of GIO prevention Ibandronate (Boniva) and Alendronate (fosamax) are not best for treatment of non-vertebral osteoporosis. While if it was osteoporosis of Wrist only, Risedronate could have been used, however, is not best for Hip Osteoporosis. Hence, only option in this case is Zoledronic acid.
Of-course Teriperatide actually helps counteract the pathogenesis of steroid on bones. 









Note: 
On treatment, if BMD T score decreases from -2.5 to -3.5, risk of fracture is doubled. On the contrary, on treatment, if BMP improves to -2.5 from -3.5, the decrease in fracture risk not only by 50 % but much more. Even as low as 0.1 improvement in BMD in wrist will lead to decrease fracture by around 50 %. 

12 million 50 yr or older has osteoporosis
1 in 2 women will have life time OP fracture (25 % spine, 15 % hip) 
1 in 5 min will have osteoporotic fractures 
Racial differences
  • Whites have higher incidence
Less than 30% of patients with hip fractures are treated with anti-osteoporsosis medication 

Bone-Density Testing Interval and Transition to oseoporosis in Older Women 
NEJM 2012
  • Moderate osteopenia (-1.5 - -- 2.00: 5 yrs
  • Severe osteopenia (-2 - -2.5): 1 yr 
  • However, this analysis did not capture the spinal osteoporosis. 
  • JAMA 2012
    • Mild osteopenia and low frax: 5-10 yr
    • Advanced osteopenia and high frax: every 2 yr
When should DEXA be repeated?
  • Controversial and unclear 
  • 1-3 yrs of therapy
  • Stay the same or slight improvement is an excellent report
  • And, when drug holiday is to be considered
What should DXA report include?
  • Manufacturar: Hologic, Lunar, Norland. Important that the same machine be used subsequent dexa scan. 
  • Images of regions of interest.
What testing should an internist obtain in a patient with newly diagnosed Low BM Density?
  • Yes: Calcium, Albumin, Mag, Phosphorous, PTH, 25 OHVit D, ALP, BUN/Cr, TSH 
    • BMD cannot differentiate osteomalacia vs osteoporosis as in hypophosphotemia, in which case no need of osteoporotic medication. Correct Phosphorous
  • Possibly: Ur Proteinuria assessment, Celiac Disease, MM, Hypogonadism, Urinary Cortisol
Medicaton associated with increased risk of osteoporosis fracture
  • Steroids, Cyclosporin, Tacrolimus, GNRH agonists, Depo-medroxyprogesterone (No estrogen leads to bone loss), Aromatase inhibitors, Tamoxifen (premenopausal women), Anticonvulsants
  • Unclear if inhaled steroids cause it. Some reports say yes, others say no. 
  • PPI, TZD, Anti-convulsants, 
Who should be treated?
  • Prior vertebral (clinical or morphometric - seen in imaging but not clinically - increased 4-5 risk of future fractures), hip, pelvic, humeral, and forearm fragility fracture (irrespective of T score). Falling from standing heights. 
Treatment options
  • 1-1.2 gm of ca (PTH < 60, or Urinary C 100-200/gm of Cr assuming not on HCTZ)
  • Aim for higher Vitamin D level (per endocrine society guidelines)
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