Bisphosphonates. Bisphosphonates inhibit bone resorption through multiple mechanisms, although the main mechanisms involve inhibiting the formation and resorptive capabilities of osteoclasts and promoting osteoclast apoptosis. ¹³ Bisphosphonates also downregulate levels of several MMPs, including MMP- 1, - 3, - 7 through - 9, and - 12 through - 14,⁶⁴ even in the periodontal ligament cells.⁶⁵ Furthermore, some bisphosphonates have anti-inflammatory properties and inhibit the release of inflammatory mediators such as IL- 6, TNF-α , and IL-1Beta.⁶⁶ Other research⁶⁷ suggests that secretion of osteocalcin by osteoblasts may also be affected by these drugs.

 

Preclinical studies^68,69 evaluating the effect of bisphosphonates on the periodontium reveal that although bisphosphonates prevent oral bone loss compared with controls, they provide no additional benefits in terms of reducing inflammation or PDs. Reddy and colleagues⁶⁸ studied the effects of alendronate on oral bone loss in 16 beagle dogs with naturally occurring periodontitis. At 6 months, alendronate resulted in a statistically significant difference in bone mass, although no differences in gingival inflammation, plaque, tooth mobility, or CAL were found when compared with controls. Similarly, another study⁶⁹ evaluated the ability of incadronate to prevent oral bone resorption in Porphyromonas gingivalis–induced periodontitis and found that it increased BMD and decreased polymorpho-

nuclear leukocyte infiltration compared with controls. Human trials^70-73 have also provided conflicting results. A recent study⁷² evaluating the effect of alendronate on ABL in 24 periodontitis patients over 6 months found that the use of this agent increased BMD, but provided no additional benefit for clinical parameters such as PD, CAL, and GI. However, a 12-month randomized controlled trial⁷¹ found different results: Bisphosphonate therapy improved clinical parameters (CAL, PD, and BOP) when compared with placebo, but did not affect periodontal bone mass. In contrast, a long-term study⁷³ of 4 women receiving intermittent cyclical doses of etidronate revealed that bisphosphonates increased BMD and decreased tooth mobility and PDs. Bisphosphonates are highly concentrated in bone tissue and remain in the body for as long as 10 years.⁷⁴ Given this long half-life and recent reports of significant side effects such as osteonecrosis of the jaw,⁷⁵ additional research is urgently needed to determine appropriate uses for these drugs. Discussion and a case report on bisphosphonate-related osteonecrosis of the jaw are presented elsewhere in this issue.⁷⁶

Receptor Activator of NF-κ (RANK), RANKL, and OPG.
Osteotrophic factors such as hormones (e.g., vitamin D3,
PTH, PTHrP), cytokines (IL- 1, - 6, - 11, and - 17), growth
factors (TNF-α, and BMP- 2) and other molecules (PGE ,

2

CD40L, and glucocorticoids) all enhance the expression of

Table 4b
Chemotherapeutic agents for systemic/oral bone loss — anabolic agents

Therapy

Mechanisms of action

Studies

Outcome

HRT/SERMs

Prevent cytokine production

Lopez-Marcos
and colleagues⁹⁹
HRT resulted in decreased PDs, less
tooth mobility, and less dental pain

Norderyd and colleagues¹⁰¹

Estrogen supplements decreased
gingival bleeding

PTH

Specific mechanism unknown;
anabolic actions in bone at
intermittent low doses

Miller and colleagues¹⁰⁴

PTH significantly increased crestal
bone levels in ovariectomized rats

Barros and colleagues¹⁰⁵

PTH decreased bone resorption and
inflammatory cell infiltrate in dogs

Padbury and colleagues¹⁰⁶

Hyperparathyroidism patients had
increased tori and exostoses, but not
increased periodontal disease
Schneider and colleagues¹⁰⁷ Intramembranous bone more
amenable than endogenous
vertebral bone to regeneration with
PTH treatment

BOP, bleeding on probing; PMN, polymorphonuclear leukocyte; PTH, parathyroid hormone