Therapies That Target the Bone Resorption/Formation Mechanism

The pathogenesis of osteoporosis-based fracture is understood to result primarily from a normal age-related shift in the balance of osteoblastic bone formation and osteoclastic resorption to where, by the age of 50, resorption occurs faster than new bone cells form.

Lifestyle modifications including dietary changes to increase calcium intake, exercise, and regular weight-bearing exercise are significant measures in the prevention of bone loss, and increasing vitamin D through dietary and supplementary sources is strongly recommended to slow bone loss associated with aging, with the addition of pharmacologic interventions as warranted.


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The Rationale for Bone Modulation Therapies: Resorptive vs Nonresorptive Agents

The majority of medical treatments for osteoporosis—including bisphosphonates, calcitonin, hormone replacement therapy (HRT), and the RANKL inhibitor denosumabare targeted at modulating this balance to prevent fractures through a reduction of bone loss.  Although certain bisphosphonates also demonstrate activity in bone remodeling, the parathyroid hormone (PTH) teriparatide is an anabolic agent that is the only therapy approved by the US Food and Drug Administration specifically designed to increase bone density. 

Despite the many pharmacologic options available, it is not yet clear whether resorptive or nonresorptive therapies are superior, as few comparative fracture end point studies have been conducted, explained Felicia Cosman, MD, former NOF clinical director, coauthor of a 2014 position paper on The Clinician’s Guide to Prevention and Treatment of Osteoporosis published by the NOF,5 and advisory board member for Rheumatology Advisor. “Teriparatide increases bone strength assessed by Finite Element Modeling (after QCT measurement) in both the spine and hip more than alendronate,” she said, adding that it is “more effective than alendronate against vertebral fractures in patients with glucocorticoid-induced osteoporosis, but there is no difference in nonvertebral fractures.” Similarly, it is “more effective than risedronate against new vertebral fractures in patients with acute painful vertebral fractures, but there is no difference in nonvertebral fractures.” 

Which Therapy is the Better Choice?

Measuring effects on BMD as an indicator of therapeutic efficacy, the anabolic effects of teriparatide would be expected to show greater benefit, although this is not entirely the case. “Teriparatide increases spine BMD over 18 months more than other medications,” Dr Cosman said, “but effects on hip BMD are similar to denosumab and alendronate. Denosumab increases BMD similarly to zoledronic acid over 3 years, but then continues to increase BMD, whereas with zoledronic acid, BMD plateaus after 3 years.” In looking at bisphosphonates, risedronate appeared a bit weaker at improving BMD, she observed.

As clinical investigation into these and other therapies continues, Dr Cosman outlined new treatment strategies she sees beginning to evolve. “I think we will start moving toward goal-directed treatment for osteoporosis, to achieve fracture-free periods of at least 5 years with BMD targets.  To accomplish this, we will be using more anabolic (bone-building) therapy early after the diagnosis of osteoporosis and will be using sequential therapy, rotating agents to take advantage of the greatest benefits with minimal exposure to pharmacology. We will be using more bisphosphonate treatment at the end of a treatment sequence to maintain bone effects.”

References

  1. Curtis EM, Moon RJ, Dennison EM, et al.  Recent advances in the pathogenesis and treatment of osteoporosis.  Clin Med (Lond). 2015;15:92-96.
  2. Office of the Surgeon General. Bone health and osteoporosis: a report of the Surgeon Generation (US) Rockville, MD.  2004. Available at: http://www.niams.nih.gov/Health_Info/Bone/SGR/SGRBoneHealth_Eng.pdf  Accessed on December 16, 2015.
  3. Weinerman S, Usera GL. Indications and outcomes of osteoporosis and bone modulation therapies. Oral Maxilofacial Surg Clin N Am. 2015;27:567-571.
  4. Poiana C, Carsote M, Radoi V, et al. Prevalent osteoporotic fractures in 622 obese and non- obese menopausal women. J Med Life. 2015:8:462-466.
  5. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis: a position paper. Osteoporosis Int.  2014;25:2359-2381.
  6. National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. 2010.