10 Minute Osteoporosis

 

This is the first chapter of a new series "10 Minute Endocrine Update". The idea is to make micro-reviews of endocronology topics to be read in 10 minutes in a post. Every post will have just 2 parts: the first is Introduction, that includes definition, epidemiology, pathophysiology, clinical presentation and diagnosis, and the other, the most important, Treatment. I want them to be very very concise, don't use 3 words if it can be said in 2. I don't want anyone but me to read it. Therefore, based in my previous experience, I thought the best strategy to keep it hidden is to write it in my blog.

OSTEOPOROSIS

 

INTRODUCTION

• Definition. Decreased bone mass and architectural disruption resulting in bone fragility and risk of fracture. It can be primary or secondary. Glucocorticoid-induced OP is not included here.
  
• Epidemiology. Estimated 200 M (2.5% of world population) and 9M OP fractures. Risk factors are:
• Unmodifiable: female sex, age, caucasian ethnicity
• Habits: smoke, alcohol, sedentary lifestyle.
  
• Medications: glucocorticoid, hormons (aromatase inhibitors, gonadotropin analogues) chemotherapy, antieconvulsivants, anticoagulants.
  
• Physiological and pathological conditions: low BMI, low calcium intake, immobilization, AR
  
• Etiology/pathophysiology
• Uncoupled bone remodelling.
  
• Postmenopausal women resorption > formation, both in cortical and cancellous bone
  
• Clinical presentation. None until fracture:
• Vertebral, the most frequent, 2/3 asymptomatic
• Hip, 15% of women and 5% of men by 80 have it. Risk raises with age, most occur >8
• Colles, shortly after menopause.
  
• Diagnosis. 
• Criteria: One of them:
• Fragility fracture: spontaneous or by minor trauma (stress fractures, due to repetitive minor trauma, is different). Most common in hip, wrist and spine. Also in ribs, humerus and pelvis. Not in skull, hands, feet, ankle or cervical spine.
  
• BMD 
• Postmenopausal women and men >50: <=2.5 SD below peak, at any site by DXA (preferred method), excluding other causes of low BMD like osteomalacia. Sites: hip and spine (this one has less variability in follow-up excluding osteophytes and vascular calcifications). Some say BMD at one site predicts FR there, other that BMD at any site predicts FR at any.
  
• Premenopausal women and men <50: not applicable, BMD not correlated to fracture risk.
• <20: not applicable, peak BMD not reached. 
• DD: osteomalacia, malignancy (myeloma), Paget, hyperparathyroidism, renal osteodystrophy.
• In CKD, diagnose OP only after excluding kidney bone disease, where secondary HPT, adynamic bone disease, osteomalacia and acidosis are frequent.
  
• Diagnostic workup: BMD, biochemistry, complete blood count, 25OHD, FRAX, other if suggested.
• Bone-turnover markers, not necessary:
• Bone formation: Alkaline Phosphatase (AP) (unspecific), Osteocalcin (OC), procolagen-1 N- and carboxiterminal propeptides (P1NP, P1CP). Best: OC and P1NP.
  
• Bone resorption: Hydroxyprolin (unspecific), pyridinolin and deoxypyridinolin, tartrate-resistant acid phosphatasa 5b (TRAP), Carboxy- and N-terminal cross-link  type 1 procollagen telopeptides (CTX-1 and NTX-1). Best CTX-1. 
• There are quite a lot of effort to estimate fracture risk (frax and stuff like that) in people with osteopenia (TSc from -2.5 to -1) cause most fractures occur in people with BMD in this range, but it smells like "big pharma seeking patients to sell drugs", because these people (people, not patients) do not have OP and are therefore beyond this review. Societies recommend drugs in osteopenia in FRAX 10y hip fracture risk >3% or overall fracture risk >20%, but treatment in this situation is not evidence-based (see later)
  

TREATMENT 

Never forget that the only aim is fracture prevention, therefore one cannot know efficiency of treatment at individual level (BMD recovery is not good predictor). 

Drugs are indicated if patient meets diagnostic criteria for osteoporosis (fragility fracture or TScore >=2.5). That includes 50% of women >65 in US. Societies also recommend it in high 10y FRAX risk, but that's not supported by clinical trials. That would increase candidates to >70% in >65y and >90% in >75y. 

No high-quality comparison between drugs is available, therefore choice of drug is not evidence-supported. Common practice is start biphosphonate except in very high risk, CKD or intolerance/contraindication, commonly an oral BP (alen- risedronate). Second choice drugs are denosumab and anabolic drugs (teri > abaloparatide > romosozumab), according to patient characteristics.

• General measures: exercise, avoid smoking and alcohol, no proven effect. Exercise reduce overall fractures in a 10-trial metaanalysis but with risk of publication bias.
  
• Calcium and vitamin D: no proven effect. Adequate intake of 1200 mg Ca and 800 IU of D is recommended and supplement is advised if low dietary intake, particularly on drug therapy.
  
• Biphosphonates. Antiresorptive agents, reduce osteoclast activity. 
• Alen- rise- (both oral) and zoledronic (IV) reduce spine, non-vertebral and hip fractures. Ibandronate (oral, IV) reduce spine fractures when oral, no RCT data for IV iban-. 
• Usual initial therapy oral (preferred) 5y, zole 3h, then no evidence-based guides (see below).
  
• Adverse effects: GI frequent when oral, flu-like in 1/3 of IV zoledronic, hypocalcemia, osteoarthralgias, jaw osteonecrosis, atypical fractures >2-3 y. 
• Avoid oral in CKD with GFR<30 mL/min, esophageal diseases, inability to stay upright and roux-en-y gastric bypass. 
  
• RANK-L inhibitors. Denosumab 60 mg SC/6m
• Effective in vertebral, non-vertebral and hip fractures.
• Rapid protection lose after discontinuation, consider need for life-long therapy or switch to other drug.
• Adverse effect: flu-like syndrome, atypical fractures, jaw osteonecrosis. 
• No first-line therapy except:
• Contraindications or intolerance to BP
• Extremely high fracture risk
• CKD
  
• Estrogen. Effective in postmenopause spine and non-vertebral fractures. Raise CV risk if initiated >10y after menopause and not indicated. Accepted soon after menopause if indicated for other reasons. 
• SERM. Raloxifene (similar bazedoxifene with less experience) reduce only spine fractures and also breast cancer. Adverse effect: worsens flushes, venous thrombosis, stroke. 
• Anabolic therapy. Not initial choice, except in high risk or intolerance for other drugs:
• Teriparatide. daily SC for 18-24 months, reduce spine and non-spine fractures better than risedronate, but not hip. Adverse effects: hypercalcemia, don't use in bone malignancies or previous RT for that reason. 
• Abaloparatide. PTH-rP analogue, daily SC. Reduces vertebral and (less) non-vertebral fractures, not hip. Less hypercalcemia than teri, but produces tachycardia. Not approved in Europe. 
• Romosozumab, sclerostin-inhibiting monoclonal Ab.
• Monthly.
• Reduces vertebral and non-vertebral fractures. 
  
• Increase CV events.
• Only one-year therapy because of lack of experience. 
• Non-recommended drugs: calcitonin, calcitriol, strontium ranelate, vitamin K, tibolone, androgens, tibolone, isoflavones, fluoride. Read technical reviews elsewhere to see explanation.
  

Monitoring:

• Common practice is repeat BMD regularly but no evidence that BMD response correlates with fracture risk. If BMD lowers on drug therapy, make sure drug and adequate Ca+vitD is being taken, if so investigate other conditions. Not evidence in this case to support decision to change or discontinue drug.
  
• Bone markers like CTX or NTX are generally not neccesary.

All RCTs are performed in postmenopausal women. Translating recommendations to men or premenopausal women means leaping from science to adventure. I prefer science. 

Combination therapy is not supported by clinical studies. 

Duration of therapy: all but biphosphonates lose protective effect after discontinuation, BP retain effect 1-2y for oral or 2-3 for IV. RCT of BP show efficacy only for trial duration (2-3y) and its extensions, but beyond 5y there is no evidence. Recommendation (expert opinion = rubbish) is to treat for 5y (oral alen-rise) or 3y (IV zole) and continue if fracture, high dose of GC or >75y. Rest of cases, individualize.

REFERENCES:

• UpToDate (my institutional subscription)
  
• Osteoporosis Current Concepts. Joints 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059859/
• Osteoporosis Lancet Jan-19. https://pdf.sciencedirectassets.com/271074/1-s2.0-S0140673619X00045/1-s2.0-S0140673618321123/main.pdf