Osteoporosis

Background

• Occurs commonly in postmenopausal women (↓ in estrogen level), which can occur as a result of normal age-related bone loss.
• Adequate Ca and vitamin D intake are important, deficiency in children can cause rickets, in adults cause osteomalacia (softening of bone)
• T score is calculated by comparing bone mineral density (BMD) to normal value, the gold standard test is dual energy x-ray absorptiometry (DEXA) scan.
• Osteoporosis: T-score < -2.5; Osteopenia: -1 -to -2.5; Normal: > -1
• Osteoblast: bone formation; Osteoclast: bone breakdown, estrogen/ raloxifene/ bisphosphonates slow down breakdown.
• Thyroid hormones: thyroid = ↑ metabolism; calcitonin = turns blood Ca²⁺into bone, ↓ blood Ca²⁺.
• Parathyroid makes parathyroid hormone (PTH), regulates Ca and phosphate. PTH = ↑ serum Ca²⁺by increasing bone resorption (osteoclast), and ↓ serum phosphate.

 

Offending drugs

• Long term steroid & PPI: ↓ Ca absorption
• Anticonvulsants (carbamazepine, fosphenytoin, phenobarb, phenytoin, primidone) MOA: mostly are Na channel blockers, some block Ca (↓Ca²⁺).
• Warfarin, heparin
• Excessive thyroid hormone (opposite effect of PTH): ↓ blood Ca²⁺.
• Loop diuretics: ↓ Ca level (thiazide the opposite).
• Aromatase inhibitor, androgen blocker: think about hormone’s protective effects on bones, Ca.

 

Ca and V-D supplement

• Ca absorption is saturable, with max absorption of 500-600 per dose. Higher dose should be divided.
• D2 (ergocalciferol) 50,000 units: used in renal insufficiency or short-term deficiency; D3 (cholecalciferol) is the preferred source.
• Constipation is the common side effect.
• Calcitriol: a synthetic active metabolite of V-D. FDA approved for hypocalcemia, hypoparathyroidism, and bone mineral disorder.
• Ca carbonate (Tums, Caltrate, Oysco): highest amount (40%) of elemental Ca.
• Ca citrate (Calcitrate): better absorption, but lower amount of elemental Ca.

 

Drug therapy for osteoporosis

• Prevention: bisphosphonate, estrogen agonist/antagonist (raloxifene, Duavee), hormonal therapy (HRT).
• Treatment: bisphosphonate, PTH analog (teriparatide), raloxifene, denosumab, and calcitonin.
• PTH analog and denosumab: high risk patients only.
• Last line: estrogen therapy (lowest dose possible), calcitonin (less effective and ↑ risk of cancer).

 

Bisphosphonates

• Drugs: alendronate (Fosamax), risedronate (Actonel, Atelvia), ibandronate (Boniva, q-month), Zoledronic acid (Reclast IV)
• MOA: inhibits osteoclast activity by preventing formation of proteins needed for osteoclast cell membrane.
• SE: esophageal ulceration, hypocalcemia; Caution: Jaw necrosis, atypical femur fracture with long term use.
• 1st line in prevention or treatment, ↑ bone density more than estrogen/raloxifene and ↓ risk of fracture.
• Ibandronate is also available IV, every 3 months. Injections are preferred for patients with esophagitis.
• Zoledronic acid: infusion 1x/yr, do not use in CrCl<35; another name for zoledronic acid (Zometa) is for hypercalcemia in malignancy, administered monthly.
• Counseling for weekly pill: empty stomach with a full glass of water 30 mins before any food/drink, remain upright 30 mins after the pill.

 

Estrogen agonist/antagonist 

• Drug: Raloxifene (Evista), conjugated estrogen/bazidoxifene (Duavee)
• MOA: estrogen agonist/antagonist (selective estrogen receptor modulator-SERM) that ↓ bone resorption.
• SE: similar to estrogen ↑ risk of VTE; vasomotor symptoms due to hormonal change (only apply to raloxifene: hot flash, mood change, bleeding/ discharge, edema, leg cramps).
• Raloxifene is for prevention and treatment in postmenopausal women; ↓ risk for breast cancer (prevention), ↑ vasomotor symptoms.
• Duavee is for prevention only and is used in postmenopausal women with a uterus; ↑ risk of cancer (endometrial, breast, ovarian), ↓ vasomotor symptoms.

 

Calcitonin (Miacalcin, Fortical)

• Antibody development from salmon, directly inhibit osteoclast bone resorption.
• Warning: hypo-Ca (The effect of calcitonin hormone turns blood Ca into bone, ↓ blood Ca), ↑ risk of malignancy with long term use, hypersensitivity reaction (derived from salmon).
• 1 spray to alternate nostril daily.

 

Parathyroid hormone (PTH) analogs

• Drugs: Teriparatide (Forteo), abaloparatide
• MOA: recombinant parathyroid hormone (PTH) with a unique MOA as an anabolic agent, stimulates osteoblast and new bone formation.
• SE: bone pain, ↑Ca; Caution in Paget's disease, hypercalcemia, osteosarcoma.
• Use in very high risk for fracture.
• 20mcg SC daily, max 2 years due to BBW: osteosarcoma.

 

Denosumab (Prolia)

• MOA: Monoclonal antibody, prevent osteoclast formation.
• Common use in osteoporosis and hypercalcemia (very common in cancer). It can also treat bone cancer and bone problems in patients who have cancer; in high risk only
• Warnings: hypocalcemia (check level before administering); warnings: osteonecrosis of jaw.
• SC Q-6mos @ clinic only.

 

Gout

 

Background

• Recurrent attacks of acute inflammatory arthritis. Symptoms include severe pain, burning, swelling, typically occurs unilaterally on one side of joints, most often ankle and feet. Joints in the big toe are common sites.
• Caused by elevated level of uric acid in the blood which crystallizes in the joints, very painful.
• Risk factors: Advanced age, male, overweight, excessive alcohol intake; HTN, renal insufficiency (unable to excrete uric acid and lead to higher levels).
• Normal UA level: 6-7 mg/dL.

 

Offending drugs (elevates UA)

• Diuretics (thiazide, loop), niacin, (cyclosporine, levodopa, pyrazinamide).

 

Acute gout attack 

Colchicine (Colcrys)

• MOA: disrupts cytoskeletal function through inhibition of tubulin polymerization, prevents activation of neutrophil that mediate gout symptoms.
• + probenecid (Colbenemid)
• SE: GI (N/V/D).
• 6mg BID followed by 1 tab in 1-hr (max: 1.8mg)
• IV form is highly toxic with a narrow therapeutic index, avoid in hepatic and renal disease.
• DI: A 3A4 substrate, avoid use with strong inhibitors.
• Can be used for both acute attack and gout prevention.

 

NSAIDS

• Indomethacin: traditional drug of choice (DOC), increased GI toxicity than ibuprofen, has psychiatric SE (meaning more lipophilic than other NSAIDs), taper down to avoid rebound attack.
• Other choices: Naproxen, sulindac (Clinoril), celecoxib (Celebrex)

 

Steroids

• Prednisone, methylprednisolone (Solu-Medrol) & triamcinolone (intra-articular inj.)

 

Prophylactic treatment

 

 Xanthine oxidase inhibitor

• Drugs: allopurinol (Zyloprim), febuxostat (Uloric)
• MOA: inhibit xanthine oxidase and block UA production; acts on purine catabolism, prevents conversion of xanthine to uric acid.
• SE: rash, GI issues, LFT.
• In general, well tolerated, watch out for allopurinol needing dose adjustment in CKD, since it is cleared through kidney.
• Uloric is expensive, advantages are: no dose adjustment in renal impairment, decreased risk of hypersensitivity reaction (↓ risk for rash compare to allopurinol).

 

Uric acid excretion enhancer

• Drug: Probenecid (Benemid, + colchicine = Colbenemid)
• MOA: uricosuric, increase UA elimination through urine.
• Require adequate renal function
• Drug interactions: it decreases renal clearance of other drugs such as: ASA, MTX, theophylline, PCN

 

Uric acid specific enzyme

• Drug: Pegloticase (Krystexxa) injection
• MOA: break down uric acid.
• IV, costly, severe infusion reaction.

 

Osteoarthritis (OA)

 

• Non-inflammatory joint disorder that can develop into inflammatory.
• Presentation and symptoms: Achy, painful joints, cracking noise or vibration at joint, bony enlargement in fingers
• Pain relieved by rest, pain relieve by hot or cold compresses
• For more severe disease: intra-articular hylan injection; Administer at doctor office (Synvisc, Supartz, Hyalgan).
• Do not confuse OA with rheumatoid arthritis, which is an inflammatory and autoimmune disorder.
• First line: acetaminophen.

 

Rheumatoid arthritis (RA)

 

Background

• Rheumatoid arthritis (RA) is an autoimmune condition.
• Chronic, symmetrical, progressive inflammation of joints and other organs (kidney, eyes, heart, lungs)
• Signs and symptoms: Morning stiffness, swelling, edema, decreased range of motion, muscle atrophy, deformity.
• Diagnoses: Symmetric presentation, morning stiffness > 1-hr, soft tissue swelling in 3 joints, swelling of hand/foot/wrist, subcutaneous modules, positive serum factor.

 

Treatment

• Mild - moderate: Disease-modifying antirheumatic drugs (DMARDs): MTX, sulfasalazine, etc.
• Severe: biologics.
• Acute RA flare-up: NSAIDs, steroids.

 

NSAIDs

• Side effects: Edema, CV, and GI, risk higher in elderly, avoid use in renal disease
• Drugs: celecoxib (Celebrex), indomethacin (Indocin).
• Cox2 selective has fewer GI effects.

 

Steroids

• Drugs: Prednisone (Deltasone)
• Steroids are like a panacea in various conditions due to their strong anti-inflammatory effect (stronger than NSAIDs), it’s important to understand their side effects.
• Short-term SE: fluid retention, mood swing, insomnia, increase glucose/BP, leukocytosis (increased white blood cell count), CNS activation.
• Long-term SE: adrenal suppression/Cushing's syndrome, impaired wound healing (lowered immune), osteoporosis.

 

Disease-modifying antirheumatic drugs (DMARDs)

• Should be started within 3 months of diagnosis, as these drugs slow down the disease process and help prevent further joint damage.
• These drugs not only can manage RA, but also have a place in other autoimmune conditions e.g. lupus.

 

Methotrexate (Rheumatrex)

• MOA: Folate antimetabolite.
• Many BBW: liver, renal, pneumonitis, alopecia, bone marrow suppression.
• SE: stomatitis, N/D, risk for infection, monitor LFT, CBC, chest x-ray, renal function at baseline
• CI: pregnancy & lactating women, SCr > 1.5, diarrhea or any infection, immunodeficiency
• Weekly dosing for RA, max: 20mg weekly. Dosing in chemotherapy is higher and can be dosed daily.
• Do not drink alcohol; Antidote: leucovorin.

 

Hydroxychloroquine (Plaquenil)

• Also used to treat antimalarial, lupus erythematosus
• SE: blurred vision, photophobia, corneal change, GI (N/V/D, take with food) ataxia, urticaria, alopecia
• Used in mild RA, take with food 200mg BID.

 

Sulfasalazine (Azulfidine)

• MOA: Impair folate absorption, give supplement.
• CI in sulfa, salicylate allergy, GI obstruction
• SE: GI, photosensitivity, yellow/orange skin discoloration
• Take with fod, and lots of water to prevent crystalluria. (500mg QD-BID)

Leflunomide (Arava)

• Anti-inflammatory, anti-proliferative, immunomodulary.
• Avoid pregnancy. If trying to conceive, wait 2 years or give cholestyramine
• SE: hepatotoxic, alopecia.

 

Biologics

• Tumor necrosis factor (TNF) inhibitors (Anti-TNF): 1st line; Non-TNF inhibitors: 2nd line

 

TNF blockers

• Drugs: Etanercept (Enbrel), Adalimumab (Humira), Infliximab (Remicade), Certolizumab (Cimzia), Golimumab (Simponi)
• MOA: Tumor necrosis factor blocker, immunosuppressive therapy. TNF plays a role in inflammation process (must be a lot stronger compared to NSAIDs or steroids).
• Indication: RA. Be flexible in your knowledge and think about their possible usage for other autoimmune disorders: psoriasis, CD-Crohn's, UC-ulcerative colitis.
• SE: LIST, L – lymphomas, I – infections, S – skin cancer, T – tuberculosis
• Caution: HF exacerbation, bone marrow suppression, hepatitis (monitor LFT)
• BBW: risk for serious infection (invasive fungal infection & TB), all patients must be evaluated for TB.
• Enbrel and Humira are self-injectable (SC) and are 1st line.
• if refrigerated then let stand to room temp prior to injection, do not expel small air bubble (may lose some of the dose), do not shake
• Do not combine with other biologics and live vaccines.
• FYI dosing:

• etanercept: 25 mg BIW, or 50mg SC weekly, may combine MTX
• Adalimumab (Humira): 40mg biweekly.
• Infliximab (Remicade): IV @ doctor office 6x/year, need filter and compatible with NS only
• Certolizumab:  200mg SC biweekly, or 400mg SC every 4 weeks.
• Golimumab: given with MTX, 50mg SC monthly, IV requires filter.

 

Other biologics:

• Orencia (abatacept - T lymphocyte inhibitor)
  • IV monthly, dosed on body weight <60kg 50mg, 60-100kg 750, >100kg 1g
• Rituximab (Rituxan):
  • IV BIM give with MTX. Pre-medicate with steroid to prevent infusion reaction.
  • Many BBW: infusion/mucocutaneous reaction, PML- progressive multifocal leukoencephalopathy (due to JC virus infection), tumor lysis.
• Actemra (tocilizumab - IL6 inhibitor): 4-8 mg/kg IV, BBW: serious infection (monitor ANC and platelet)
• Kineret (anakinra)
  • IL-1 receptor antagonist: 100 mg SC QD
  • SE: neutropenia (monitor CBC)

 

NAPLEX takeaway:

• There are so many biologics, we won’t be able to memorize them all especially when we don’t practice in the autoimmune field. It’s important to know what conditions count as autoimmune disorders, and what agents are immunosuppressive (from mild steroids to strong biologics).
• It is also essential to know the side effects of using a biologic, think in the big picture in terms of what will happen if your immune system is compromised. More infection risks! And if a drug can potentially lead to TB, one of the worst form of infections, then the immunosuppressive effects must be very potent.

 

Quiz

1. Humira is NOT indicated for which of the following?

A. Rheumatoid arthritis
b. Psoriatic arthritis
c. Ankylosing spondylitis
d. Crohn's disease
e. Irritable Bowel Syndrome

 

2. Etanercept carries the following health risks, which must be conveyed to the patient: (Select ALL that apply.)
   1. Teratogenicity
   2. Liver damage
   3. Exacerbation of heart failure
   4. Risk of infection
   5. Reactivation of latent TB

 

3. Which of the following is NOT correctly matched with its trade name?

A.Methotrexate – Rheumatrex

B.Hydroxychloroquine – Azulfidine

C.Leflunomide – Arava

D.Etanercept – Enbrel

E.Infliximab – Remicade

 

4. A 60-year-old woman on etanercept 50 mg subcutaneously once weekly is requesting that her immunizations be updated. Which immunization would be contraindicated?

A.Varicella zoster

B.Seasonal influenza vaccine (intramuscular)

C.23-valent pneumococcal vaccine

D.Tetanus, diphtheria, pertussis (Tdap)

 

 

5. A 44-year-old woman is newly diagnosed with rheumatoid arthritis (determined to be moderate– high disease activity) following more than 3 months of bilateral symptoms involving her metacarpophalangeal (MCP) and wrist joints. Laboratory results include AST 33 IU/L, ALT 36 IU/L, SCr 1.0 mg/dL, Hgb 13 g/dL, Hct 39%, (+) RF. Which is the most appropriate therapy selection?

A.Hydroxychloroquine

B.Methotrexate

C.Leflunomide

D.Adalimumab

 

6. A 56-year-old woman with rheumatoid arthritis complains of worsening joint pain in wrists and elbows over the past month. Upon physical exam, new rheumatoid nodules are noted on both elbows. Current medications include adalimumab, methotrexate, and folic acid. Prior medications include hydroxychloroquine (in combination with methotrexate), leflunomide, and etanercept. Which is the most appropriate therapy recommendation?

A.Replace adalimumab with abatacept

B.Replace methotrexate with sulfasalazine

C.Add sulfasalazine

D.Add minocycline

 

7. A 63-year-old asymptomatic man with a medical history significant for hypertension and obesity takes bisoprolol 5 mg daily. His serum uric acid concentration is 7.3 mg/dL on routine laboratory examination. Which is the most appropriate therapeutic strategy?

A.Start allopurinol 100 mg/day.

B.Start febuxostat 40 mg/day.

C.Start probenecid 500 mg twice daily.

D.Therapy is not indicated because the patient has not yet experienced a gout attack.

 

 

8. A 55 yo man with a medical history of hypertension, obesity, and gout (one episode, 6 months ago), takes enalapril 40 mg daily, amlodipine 10 mg daily, and ASA 81 mg daily. He presents with symptoms of gout, this morning, of his left first metatarsophalangeal joint and left ankle. The metatarsophalangeal joint is swollen, inflamed, erythematous, and sensitive to light touch. Which is the best approach to therapy?

A.Colchicine 1.2 mg by mouth, then 0.6 mg 1 hour later

B.Colchicine 1.2 mg by mouth, then 0.6 mg 1 hour later; initiate allopurinol 300 mg once daily

C.Colchicine 1.2 mg by mouth, then 0.6 mg every hour PRN as tolerated

D.Colchicine 1.2 mg by mouth, then 0.6 mg every hour PRN as tolerated; start allopurinol 300 mg once daily

 

 Answers

1. (e). Humira (Adalimumab) is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF).
2. B C D E.  Liver monitoring, warnings: serious infections and malignancies (remember LIST) L – lymphomas, I – infections , S – skin cancer, T – tuberculosis; Do not shake; refrigerate; bring to room temp before injecting (to reduce pain).
3. Hydroxychloroquine is generic for Plaquenil. Azulfidine is the brand name for sulfasalazine. The other answer choices are correctly matched with their trade names. Methotrexate (A) is generic for Rheumatrex or Trexall.
4. Patients with RA receiving biologic DMARDs should not be administered live vaccines such as varicella zoster. Trivalent seasonal influenza vaccine and 23-valent pneumococcal vaccine are acceptable to give to all patients. The Tdap vaccine may also be safely administered to patients who are considered (non-HIV) immune compromised or receiving immune system– compromising agents.
5. Treatment-naive patients with moderate– high disease activity should receive combination DMARD therapy with methotrexate unless contraindicated.
6. Based upon the 2015 ACR recommendations for rheumatoid arthritis treatment in patients with established disease, health care providers should replace adalimumab in patients with high disease activity (persistently worsening symptoms on escalating therapy); the options include an alternate anti-TNF agent, rituximab, or abatacept. Using an alternate nonbiologic DMARD such as sulfasalazine in place of (B) or in addition to methotrexate (C) would not likely alter the disease progression or symptoms at this stage. Minocycline is reserved for patients with low disease activity and good prognostic features.
7. Patients should not receive treatment for asymptomatic hyperuricemia until they have experienced their first gout attack. 1-2 weeks after the first attack, patients may begin uric acid– lowering therapy, and they should be treated to a serum uric acid concentration of <6 mg/dL.
8. Because this patient is suffering from an acute gouty attack, the use of allopurinol is not appropriate. Allopurinol should be initiated only after the episode of acute gout has resolved. With respect to the colchicine dose, current recommendations support the lower cumulative dose due to equal efficacy and superior tolerability (fewer GI adverse events). The “as-tolerated” put the patient at risk of overdosing and could potentially cause GI adverse effects.

 

 

 

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