Disease Analysis: Osteoporosis

Disease Overview

Osteoporosis is the most common metabolic bone disease, and is characterized by compromised bone strength which predisposes individuals to an increased risk of fracture. Bone strength itself is not directly measurable, but can be inferred from bone mass and quality, with bone mass being most commonly approximated by assessing bone mineral density (BMD). A person with a BMD measurement that falls within one standard deviation (SD) of the healthy reference (30-year-old male or female) is considered to have healthy bone mass and structure (T-score >-1).

Latest key takeaways

• Datamonitor Healthcare estimates that in 2021, there were 374.3 million prevalent cases of osteoporosis among adults aged 50 years and older worldwide, and forecasts that number to increase to 427.8 million prevalent cases by 2027.
• While first-line bisphosphonates are generically available, and biosimilars/synthetic peptide generics to the first anabolic therapy, Forteo, started to be introduced in 2019, the branded osteoporosis market has continued to grow, driven by Amgen’s market-leading Prolia, and to a lesser degree by novel anabolics with efficacy and convenience advantages over Forteo. Growth is expected to continue for another few years, at least in major developed markets, until biosimilars to Prolia are introduced.
• Bisphosphonates reduce bone resorption and have a variety of convenient dosing options, including oral and up to yearly IV. They started to become generic in the first decade of the 2000s, but in the same time frame had publicized news on safety findings, which led to a decline in their use, at least in some geographies (such as the US), though they are still the most used drugs. At least partly due to safety issues, but also because bone mineral density (BMD) only gradually declines when the drugs are stopped, patients are recommended to be evaluated for a potential drug holiday after 3–5 years, or later, depending on the agent and patient’s fracture risk.
• Market-leader Prolia has continued to be an important growth driver, despite being first approved in 2010. While it works by reducing bone resorption, like the bisphosphonates, Prolia has some evidence for stronger increases in BMD, though there are divided opinions about using it first-line, due to a more rapid drop in BMD and increased risk of vertebral fractures after discontinuation, requiring indefinite treatment or switching to an alternative treatment. Amgen also touts its dosing, which involves an injection every six months by a provider. Relative to anabolic agents, which stimulate bone formation but are used for a limited duration and require daily or monthly injections, Prolia has benefited from clearly advantageous dosing, no limitations on length of use, and flexible positioning as an alternative initial therapy for high-fracture-risk osteoporosis or bisphosphonate intolerance/failure ‒ or, like bisphosphonates, as a follow-on option after completion of anabolic therapy. It also costs less, has reimbursement advantages in the US as a provider-administered drug, and benefits from co-marketing with Amgen’s anabolic Evenity. Sales growth appeared to plateau in 2020, but that may have been due to the COVID-19 pandemic, as it picked up again in 2021. While growth is likely to continue in the near term, patent expirations in the US and other major markets in 2025 will open the door to biosimilars.
• Anabolic agents are relegated to severe osteoporosis or patients who cannot tolerate/fail bisphosphonates, due to the need for daily or monthly injections, limited duration of use (which in turn is due to safety concerns and lack of longer-term testing or waning efficacy, depending on the agent), and associated high cost. Forteo (Eli Lilly), Teribone (Asahi Kasei) in Japan, and the more recent Tymlos (Radius Health) generally have label recommendations to limit use to two years in a patient’s lifetime, due to concerns over osteosarcoma seen preclinically. Evenity (Amgen) has warnings for increased cardiovascular risk, though there is debate over whether the risk is real, and the issue has not impacted it as much as might be expected. Evenity is still limited to a year’s use at a time, due to waning efficacy, though at the same time, it has an advantage of building bone rapidly in that time frame. Both Evenity and Tymlos have evidence for greater increases in BMD than Forteo, with Evenity’s data somewhat stronger. However, anabolics need to be followed by antiresorptive agents to maintain gains.
• Market dynamics for the anabolics have varied according to geography. In the US, both Tymlos and Evenity have net pricing lower than Forteo, yet despite an initial decline in segment sales in 2018 related to the introduction of Tymlos, with subsequent growth of these novel agents and limited penetration of the follow-on teriparatide Bonsity (Alvogen), sales in the branded segment have been modestly increasing. However, synthetic peptide generics for teriparatide, if approved, could have more impact. Evenity has surpassed Tymlos in sales, with a reimbursement advantage as a provider-administered drug, co-marketing with Prolia, and the more convenient dosing. Of concern for Tymlos, new patients have started to drop, and it is unclear if that will be a growing trend, due to the competition, though Radius is looking for some relief for its product via a label expansion for use in osteoporotic men. In the major European markets, sales of the branded segment have declined slightly, but if including biosimilars/generics to Forteo then they have been relatively flat. Evenity has only reached reimbursement agreements so far in two of the five major European markets, so uptake has been limited. Tymlos is yet to be approved, after an earlier rejection, though due to competition (including teriparatide biosimilars/generics), it may not have major gains, though it will be interesting to see if it prices aggressively low to gain better access. In Japan, sales of the branded segment have been modestly increasing, with Evenity seeing rapid uptake. Tymlos needs to work out a dosing issue before being launched, but will also face competition from more convenient weekly Teribone, which has been growing, but which may also face a biosimilar, if the biosimilar sponsor decides to launch despite pending litigation.
• While Radius Health was hoping to overcome the drawback of daily injections by developing a transdermal formulation of Tymlos, it failed to show non-inferiority with the injected formulation and was suspended. Oral formulations of teriparatide are in early-stage development, and it is unclear whether they will measure up to the injectables.
• The overall likelihood of approval of a Phase I osteoporosis asset is 4.9%, and the average probability a drug advances from Phase III is 68.4%. Osteoporosis drugs, on average, take 10.6 years from Phase I to approval, versus 9.9 years in the overall endocrine space.